Mechanisms of Antibiotic Resistance

May combine two claims.

Changes in permeability through porin alteration mechanisms frequently result in low-level resistance and are often associated with other resistance mechanisms such as increased efflux pump expression.

“Importantly, changes in permeability through any of these mechanisms frequently result in low-level resistance and are often associated with other mechanisms of resistance, such as increased expression of efflux pumps (see below) (39).”

• cites [39] Nikaido H Molecular basis of bacterial outer membrane permeability revisited Microbiol Mol Biol Rev 2003 12 67 4 593 656 14665678 PMC309051 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Carbapenemases can be divided into serine carbapenemases (Ambler class A or D) and metallo-carbapenemases (Ambler class B enzymes).

“These enzymes can be divided into serine carbapenemases (Ambler class A or D) and metallo-carbapenemases (Ambler class B enzymes).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

From an evolutionary perspective, bacteria use two major genetic strategies to adapt to the antibiotic attack: mutations in genes often associated with the mechanism of action of the compound, and acquisition of foreign DNA coding for resistance determinants through horizontal gene transfer.

“From an evolutionary perspective, bacteria use two major genetic strategies to adapt to the antibiotic “attack”, i) mutations in gene(s) often associated with the mechanism of action of the compound, and ii) acquisition of foreign DNA coding for resistance determinants through horizontal gene transfer (HGT).”

May combine two claims.

Alterations of porins can be achieved by three general processes: a shift in the type of porins expressed, a change in the level of porin expression, and impairment of porin function.

“Alterations of porins could be achieved by 3 general processes, i) a shift in the type of porins expressed, ii) a change in the level of porin expression, and iii) impairment of the porin function.”

• cites [39] Nikaido H Molecular basis of bacterial outer membrane permeability revisited Microbiol Mol Biol Rev 2003 12 67 4 593 656 14665678 PMC309051 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Bacteria have developed mechanisms to prevent the antibiotic from reaching its intracellular or periplasmic target by decreasing the uptake of the antimicrobial molecule, and this mechanism is particularly important in gram-negative bacteria.

“Bacteria have developed mechanisms to prevent the antibiotic from reaching its intracellular or periplasmic target by decreasing the uptake of the antimicrobial molecule. This mechanism is particularly important in gram-negative bacteria (for the reason specified above), limiting the influx of substances from the external milieu.”

May combine two claims.

AAC(6′)APH(2′′) is a bifunctional enzyme that confers high-level resistance to all aminoglycosides except streptomycin and accounts for most high-level gentamicin resistance detected in enterococci and methicillin-resistant S. aureus worldwide.

“Furthermore, the presence of this bifunctional enzyme accounts for most of high-level gentamicin resistance detected in enterococci (including in vancomycin-resistant strains) and methicillin-resistant S. aureus worldwide (13).”

• cites [13] Hollenbeck BL Rice LB Intrinsic and acquired resistance mechanisms in enterococcus Virulence 2012 8 15 3 5 421 33 23076243 PMC3485979 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Class C β-lactamases confer resistance to all penicillins and cephalosporins, including cephamycins, do not reliably hydrolyze aztreonam, and are not inhibited by clavulanic acid.

“Class C β-lactamases confer resistance to all penicillins and cephalosporins (although cefepime is usually a poor substrate), including cephamycins. They do not reliably hydrolyze aztreonam and are not inhibited by clavulanic acid.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The World Health Organization has named antibiotic resistance as one of the three most important public health threats of the 21st century.

“In fact, the World Health Organization has named antibiotic resistance as one of the three most important public health threats of the 21st century (1).”

• cites [1] Antimicrobial resistance: global report on surveillance 2014 World Health Organization 2014 Downloaded from http://www.who.int/drugresistance/documents/surveillancereport/en/, last accessed on March 4, 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The Bush-Jacoby classification divides β-lactamases into 4 categories according to their biochemical function, mainly based on substrate specificity.

“On the other hand, the Bush-Jacoby classification divides β-lactamases into 4 categories (each with several subgroups) according to their biochemical function, mainly based on substrate specificity (19, 20).”

• cites [19] Bush K The ABCD’s of β-lactamase nomenclature J Infect Chemother 2013 8 19 4 549 59 23828655 sourceNot checked yet

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• cites [20] Bush K Jacoby GA 2010 Updated functional classification of β-Lactamases Antimicrob Agents Chemother 54 969 976 19995920 PMC2825993 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The development of acquired resistance can be the result of mutations in chromosomal genes or due to the acquisition of external genetic determinants of resistance.

“As it will be discussed later in the chapter, the development of acquired resistance can be the result of mutations in chromosomal genes or due to the acquisition of external genetic determinants of resistance, likely obtained from intrinsically resistant organisms present in the environment.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Infections caused by multidrug-resistant organisms carry an economic burden estimated at over 20 billion dollars per year in the US alone.

“Infections caused by multidrug-resistant (MDR) organisms are associated with increased mortality compared to those caused by susceptible bacteria and they carry an important economic burden, estimated at over 20 billion dollars per year in the US only (2,3,4).”

• cites [2] Cosgrove SE The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs Clin Infect Dis 2006 1 15 42 Suppl 2 S82 9 16355321 sourceNot checked yet

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• cites [3] DiazGranados CA Zimmer SM Klein M Jernigan JA Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis Clin Infect Dis 2005 8 1 41 3 327 33 16007529 sourceNot checked yet

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• cites [4] Sydnor ER Perl TM Hospital epidemiology and infection control in acute-care settings Clin Microbiol Rev 2011 1 24 1 141 73 21233510 PMC3021207 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The Ambler classification relies on amino acid sequence identity and separates β-lactamases into 4 groups (A, B, C, and D).

“First, the Ambler classification relies on amino acid sequence identity and separates β-lactamases into 4 groups (A, B, C, and D).”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Most antimicrobial compounds are naturally produced molecules, and co-resident bacteria have evolved mechanisms to overcome their action in order to survive.

“Most antimicrobial compounds are naturally-produced molecules, and, as such, co-resident bacteria have evolved mechanisms to overcome their action in order to survive.”

Probably not a substantial claim: may not pass S3 (load-bearing).

KPC was first reported in 1996 from a K. pneumoniae recovered from a patient in North Carolina, USA.

“KPC was first reported in 1996 from a K. pneumoniae recovered from a patient in North Carolina, USA (25).”

• cites [25] Yigit H Queenan AM Anderson GJ Domenech-Sanchez A Biddle JW Steward CD Alberti S Bush K Tenover FC Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae Antimicrob Agents Chemother 2001 4 45 4 1151 61 11257029 PMC90438 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Antimicrobial resistance is ancient and is the expected result of the interaction of many organisms with their environment.

“First, antimicrobial resistance is ancient and it is the expected result of the interaction of many organisms with their environment.”

May combine two claims. The quote only partly states this claim.

NDM-1 rapidly spread around the globe and its presence is frequently accompanied by a multidrug-resistant phenotype.

“Nevertheless, NDM-1 rapidly spread around the globe, becoming a prime example of how a resistance determinant can readily disseminate worldwide despite many efforts to avoid its transmission.”

• Also stated in: § I. Modifications of the Antibiotic Molecule · plain

  “Thus, the presence of NDM-1 is frequently accompanied by a multidrug-resistant phenotype.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Classically, bacteria acquire external genetic material through three main strategies: transformation, transduction, and conjugation.

“Classically, bacteria acquire external genetic material through three main strategies, i) transformation (incorporation of naked DNA), ii) transduction (phage mediated) and, iii) conjugation (bacterial “sex”).”

May combine two claims.

Resistance to one antimicrobial class can usually be achieved through multiple biochemical pathways, and one bacterial cell may be capable of using a cadre of mechanisms of resistance to survive the effect of an antibiotic.

“Of note, resistance to one antimicrobial class can usually be achieved through multiple biochemical pathways, and one bacterial cell may be capable of using a cadre of mechanisms of resistance to survive the effect of an antibiotic.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The Centers for Disease Control and Prevention conservatively estimates that at least 23,000 people die annually in the USA as a result of an infection with an antibiotic-resistant organism.

“The Centers for Disease Control and Prevention conservatively estimates that at least 23,000 people die annually in the USA as a result of an infection with an antibiotic-resistant organism (5).”

• cites [5] Antibiotic Resistance Threats in the United States Centers for Disease Control and Prevention 2013 Downloaded from http://www.cdc.gov/drugresistance/threat-report-2013/index.html, last accessed on March 9, 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Class D β-lactamases include a wide range of enzymes initially differentiated from class A penicillinases due to their ability to hydrolyze oxacillin and because they were poorly inhibited by clavulanic acid.

“Class D β-lactamases include a wide range of enzymes that were initially differentiated from the class A penicillinases due to their ability to hydrolyze oxacillin (hence their name) and because they were poorly inhibited by clavulanic acid.”

May combine two claims.

Acquisition of foreign DNA material through horizontal gene transfer is one of the most important drivers of bacterial evolution and is frequently responsible for the development of antimicrobial resistance.

“Acquisition of foreign DNA material through HGT is one of the most important drivers of bacterial evolution and it is frequently responsible for the development of antimicrobial resistance.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Antibiotic resistance is estimated to cause around 300 million premature deaths by 2050, with a loss of up to $100 trillion to the global economy.

“Moreover, according to a recent report, antibiotic resistance is estimated to cause around 300 million premature deaths by 2050, with a loss of up to $100 trillion (£64 trillion) to the global economy (6).”

• cites [6] Antimicrobial Resistance: Tackling a Crisis for the Future Health and Wealth of Nations 2014 Downloaded from http://amr-review.org/, last accessed on March 11, 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The predominant mechanism of resistance to β-lactams in gram-negative bacteria is the production of β-lactamases, whereas resistance to these compounds in gram-positive organisms is mostly achieved by modifications of their target site, the penicillin-binding proteins.

“For example, the predominant mechanism of resistance to β-lactams in gram-negative bacteria is the production of β-lactamases, whereas resistance to these compounds in gram-positive organisms is mostly achieved by modifications of their target site, the penicillin-binding proteins (PBPs).”

May combine two claims.

The expression of ampC is generally inducible and is under strict control of a complex regulatory mechanism that has been best studied in Enterobacter spp.

“The expression of ampC is generally inducible and is under strict control of a complex regulatory mechanism that has been best studied in Enterobacter spp.”

May combine two claims.

Conjugation uses mobile genetic elements as vehicles to share genetic information, although direct transfer from chromosome to chromosome has also been well characterized.

“As a general rule, conjugation uses mobile genetic elements (MGEs) as vehicles to share valuable genetic information, although direct transfer from chromosome to chromosome has also been well characterized (9).”

• cites [9] Manson JM Hancock LE Gilmore MS Mechanism of chromosomal transfer of Enterococcus faecalis pathogenicity island, capsule, antimicrobial resistance, and other traits Proc Natl Acad Sci U S A 2010 7 6 107 27 12269 74 20566881 PMC2901427 sourceNot checked yet

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May combine two claims.

The development of newer generations of β-lactams has systematically been followed by the rapid appearance of enzymes capable of destroying any novel compound that reaches the market, a process that is a prime example of antibiotic-driven adaptive bacterial evolution.

“From then on, the development of newer generations of β-lactams has systematically been followed by the rapid appearance of enzymes capable of destroying any novel compound that reach the market, in a process that is a prime example of antibiotic-driven adaptive bacterial evolution.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Integrons are site-specific recombination systems capable of recruiting open reading frames in the form of mobile gene cassettes.

“Finally, one of the most efficient mechanisms for accumulating antimicrobial resistance genes is represented by integrons, which are site-specific recombination systems capable of recruiting open reading frames in the form of mobile gene cassettes.”

May combine two claims.

Antimicrobial resistance among common bacterial pathogens is increasing and threatens the therapeutic accomplishments of modern medicine.

“Unfortunately, the marked increase in antimicrobial resistance among common bacterial pathogens is now threatening this therapeutic accomplishment, jeopardizing the successful outcomes of critically ill patients.”

May combine two claims.

Aminoglycoside modifying enzymes covalently modify the hydroxyl or amino groups of the aminoglycoside molecule and have become the predominant mechanism of aminoglycoside resistance worldwide.

“One of the best examples of resistance via modification of the drug is the presence of aminoglycoside modifying enzymes (AMEs) that covalently modify the hydroxyl or amino groups of the aminoglycoside molecule. Multiple AMEs have been described to date and they have become the predominant mechanism of aminoglycoside resistance worldwide.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Carbapenemases are a diverse group of β-lactamases with the ability to hydrolyze carbapenems, the most potent β-lactams available in clinical practice.

“Other clinically relevant group of enzymes is the carbapenemases (a diverse group of β-lactamases with the ability to hydrolyze carbapenems), the most potent β-lactams available in clinical practice.”

May combine two claims.

CTX-M did not derive from TEM or SHV; current evidence suggests it was likely acquired from Kluyvera spp. through horizontal gene transfer.

“In contrast to other Ambler class A ESBLs like TEM-3, this enzyme did not derive from TEM or SHV, rather, the current evidence suggests that it was likely acquired from Kluyvera spp. (an environmental bacterium with no major human pathogenic significance) through HGT (22).”

• cites [22] Bonnet R Growing group of extended-spectrum beta lactamases: the CTX-M enzymes Antimicrob Agents Chemother 2004 1 48 1 1 14 14693512 PMC310187 sourceNot checked yet

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May combine two claims.

Fluoroquinolone resistance can occur due to three different biochemical routes, all of which may coexist in the same bacteria at a given time: mutations in genes encoding the target site, over-expression of efflux pumps, and protection of the fluoroquinolone target site by a protein designated Qnr.

“As an example, fluoroquinolone (FQ) resistance can occur due to three different biochemical routes, all of which may coexist in the same bacteria at a given time (producing an additive effect and, often, increasing the levels of resistance), i) mutations in genes encoding the target site of FQs (DNA gyrase and topoisomerase IV), ii) over-expression of efflux pumps that extrude the drug from the”

May combine two claims.

Most clinically relevant genes involved in target protection are carried by MGEs, although some target-protection determinants are found in the bacterial chromosome.

“Although some of the genetic determinants coding for proteins that mediate target protection have been found in the bacterial chromosome, most of the clinically relevant genes involved in this mechanism of resistance are carried by MGEs.”

May combine two claims.

The cfr gene is a plasmid-borne determinant initially described in 2000 in a bovine isolate of Staphylococcus sciuri and first reported in humans in 2005 in an S. aureus isolated from a patient in Colombia.

“The cfr gene is a plasmid-borne determinant initially described in 2000 in a bovine isolate of Staphylococcus sciuri and first reported in humans in 2005 in an S. aureus isolated from a patient in Colombia (66).”

• cites [66] Toh SM Xiong L Arias CA Villegas MV Lolans K Quinn J Mankin AS Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid Mol Microbiol 2007 64 6 1506 14 17555436 PMC2711439 sourceNot checked yet

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May combine two claims.

High-level RIF resistance occurs by single-step point mutations resulting in amino acid substitutions in the rpoB gene, and many different genetic changes have been reported.

“High-level RIF resistance has been shown to occur by single-step point mutations resulting in amino acid substitutions in the rpoB gene and many different genetic changes have been reported.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Introducing modifications to the target site is one of the most common mechanisms of antibiotic resistance in bacterial pathogens, affecting almost all families of antimicrobial compounds.

“Introducing modifications to the target site is one of the most common mechanisms of antibiotic resistance in bacterial pathogens affecting almost all families of antimicrobial compounds.”

May combine two claims.

These rpoB mutations result in decreased affinity of the drug for its target but usually spare the catalytic activity of the polymerase, permitting transcription to continue.

“Of note, while these mutations result in decreased affinity of the drug for its target, they usually spare the catalytic activity of the polymerase, permitting transcription to continue (58).”

• cites [58] Floss HG Yu TW Rifamycin-mode of action, resistance, and biosynthesis Chem Rev 2005 2 105 2 621 32 15700959 sourceNot checked yet

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May combine two claims.

K. pneumoniae post-therapy isolates exhibit a shift in porin expression from OmpK35 to OmpK36, the latter having a smaller channel size.

“The post-therapy isolates were found to exhibit a shift in porin expression from OmpK35 to OmpK36 (the latter possessing a smaller channel size).”

• cites [41] Hasdemir UO Chevalier J Nordmann P Pagès JM Detection and prevalence of active drug efflux mechanism in various multidrugresistant Klebsiella pneumoniae strains from Turkey J Clin Microbiol 42 2701 2706 2004 15184455 PMC427859 sourceNot checked yet

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• cites [42] Doménech-Sánchez A Martínez-Martínez L Hernández-Allés S del Carmen Conejo M Pascual A Tomás JM Albertí S Benedí VJ Role of Klebsiella pneumoniae OmpK35 porin in antimicrobial resistance Antimicrob Agents Chemother 47 3332 3335 2003 14506051 PMC201126 sourceNot checked yet

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May combine two claims.

TetO competes with tetracycline for the same ribosomal space and alters the geometry of the antibiotic binding site, displacing the molecule from the ribosome and allowing protein synthesis to resume.

“Similarly, TetO has also been shown to compete with tetracycline for the same ribosomal space and to alter the geometry of the binding site of the antibiotic, displacing the molecule from the ribosome and allowing protein synthesis to resume (53).”

• cites [53] Li W Atkinson GC Thakor NS Allas U Lu CC Chan KY Tenson T Schulten K Wilson KS Hauryliuk V Frank J Mechanism of tetracycline resistance by ribosomal protection protein Tet(O) Nat Commun 2013 4 1477 23403578 PMC3576927 sourceNot checked yet

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May combine two claims.

Tet(M) was initially described in Streptococcus spp. and Tet(O) in Campylobacter jejuni, but both are now widely distributed among bacterial species, likely because they are found in plasmids and broad-range conjugative transposons.

“Tet(M) was initially described in Streptococcus spp. and Tet(O) in Campylobacter jejuni, but they are now both widely distributed among different bacterial species, likely because they have been found in several plasmids and in broad-range conjugative transposons (51).”

• cites [51] Connell SR Tracz DM Nierhaus KH Taylor DE Ribosomal protection proteins and their mechanism of tetracycline resistance Antimicrob Agents Chemother 2003 12 47 12 3675 81 14638464 PMC296194 sourceNot checked yet

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May combine two claims.

Many Tet pumps affect tetracycline and doxycycline but do not decrease minocycline or tigecycline susceptibility, because they cannot use these compounds as substrates.

“Importantly, many of these pumps affect tetracycline and doxycycline, but do not decrease minocycline or tigecycline susceptibility, as they are not able to use these compounds as substrates (44, 47).”

• cites [44] Poole K Efflux-mediated antimicrobial resistance J Antimicrob Chemother 2005 7 56 1 20 51 15914491 sourceNot checked yet

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• cites [47] Roberts MC Update on acquired tetracycline resistance genes FEMS Microbiol Lett 2005 4 15 245 2 195 203 15837373 sourceNot checked yet

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May combine two claims.

Clinically relevant fluoroquinolone resistance frequently requires accumulation of genetic changes over time, with the first mutation producing minor increases in MIC.

“Thus, in contrast to the case of RIF, clinically relevant FQ resistance frequently requires an accumulation of genetic changes over time, with the first mutation producing minor increases in the MIC (59).”

• cites [59] Hooper DC Fluoroquinolone resistance among Gram-positive cocci Lancet Infect Dis 2002 9 2 9 530 8 12206969 sourceNot checked yet

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May combine two claims.

Methicillin resistance in S. aureus results from acquisition of the foreign gene mecA, often located in SCCmec.

“Resistance to methicillin (a semisynthetic penicillin stable against the staphylococcal penicillinase) in S. aureus results from the acquisition of a foreign gene (likely from Staphylococcus sciuri) designated mecA often located in a large DNA fragment designated staphylococcal chromosomal cassette mec (SCCmec).”

May combine two claims.

Crystallographic studies show that AcrB has two binding pockets with different substrate preferences and that compounds are moved out through conformational changes in a functionally rotating mechanism ending with extrusion via TolC, requiring interaction with AcrA.

“Indeed, they have shown that AcrB has two binding pockets with different substrate preferences and that compounds are moved out of the cell through a series of conformational changes in a functionally rotating mechanism that finishes with the substrate being extruded via TolC (a process that requires an interaction with the periplasmic accessory protein AcrA) (Du D Nature 2014).”

• cites Du D Nature 2014Not checked yet

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May combine two claims.

RIF binding pocket is a highly conserved structure in the beta subunit of RNA polymerase encoded by rpoB, and after binding the antibiotic interrupts transcription by blocking the path of the nascent RNA.

“RIF binding pocket is a highly conserved structure located in the β subunit of the RNA polymerase (encoded by rpoB), and after binding, the antibiotic molecule interrupts transcription by directly blocking the path of the nascent RNA (57).”

• cites [57] Campbell EA Korzheva N Mustaev A Murakami K Nair S Goldfarb A Darst SA Structural mechanism for rifampicin inhibition of bacterial rna polymerase Cell 2001 3 23 104 6 901 12 11290327 sourceNot checked yet

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May combine two claims.

Target changes may consist of point mutations in genes encoding the target site, enzymatic alterations of the binding site, and/or replacement or bypass of the original target.

“These target changes may consist of i) point mutations in the genes encoding the target site, ii) enzymatic alterations of the binding site (e.g. addition of methyl groups), and/or iii) replacement or bypass of the original target.”

May combine two claims.

Efflux systems may be substrate-specific or have broad substrate specificity, and broad-specificity systems are usually found in MDR bacteria.

“These systems may be substrate-specific (for a particular antibiotic such as tet determinants for tetracycline and mef genes for macrolides in pneumococci) or with broad substrate specificity, which are usually found in MDR bacteria (44).”

• cites [44] Poole K Efflux-mediated antimicrobial resistance J Antimicrob Chemother 2005 7 56 1 20 51 15914491 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

There are five major families of efflux pumps: MFS, SMR, RND, ABC and MATE.

“There are 5 major families of efflux pumps, including i) the major facilitator superfamily (MFS), ii) the small multidrug resistance family (SMR), iii) the resistance-nodulation-cell-division family (RND), iv) the ATP-binding cassette family (ABC), and v) the multidrug and toxic compound extrusion family (MATE).”

• cites [46] Piddock LJ Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria Clin Microbiol Rev 2006 4 19 2 382 402 16614254 PMC1471989 sourceNot checked yet

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May combine two claims.

TetM directly dislodges and releases tetracycline from the ribosome by interaction between domain IV of the 16S rRNA and the tetracycline binding site, and this interaction alters ribosomal conformation, preventing rebinding of the antibiotic.

“Dönhöfer et al. recently showed that TetM directly dislodges and releases tetracycline from the ribosome by an interaction between the domain IV of the 16S rRNA and the tetracycline binding site. Furthermore, this interaction alters the ribosomal conformation, preventing rebinding of the antibiotic (52).”

• cites [52] Dönhöfer A Franckenberg S Wickles S Berninghausen O Beckmann R Wilson DN Structural basis for TetM-mediated tetracycline resistance Proc Natl Acad Sci USA 2012 10 16 109 42 16900 5 23027944 PMC3479509 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

To date, nine distinct enterococcal van clusters have been described: vanA, vanB, vanC, vanD, vanE, vanG, vanL, vanM and vanN.

“To date, nine distinct enterococcal van clusters have been described (vanA, vanB, vanC, vanD, vanE, vanG, vanL, vanM and vanN).”

Probably not a substantial claim: may not pass S3 (load-bearing).

It has been postulated that the main effect of vancomycin binding to D-Ala-D-Ala-ending precursors is alteration of transglycosylation, presumably by steric hindrance, preventing further processing of the cell wall and leading to bacterial death.

“It has been postulated that the main effect of the binding of vancomycin to D-Ala-D-Ala-ending precursors emerging from the cytoplasm is alteration of transglycosylation (presumably due to steric hindrance) preventing further processing of the cell wall and leading to bacterial death (72).”

• cites [72] Reynolds PE Structure, biochemistry and mechanism of action of glycopeptide antibiotics Eur J Clin Microbiol Infect Dis 1989 11 8 11 943 50 2532132 sourceNot checked yet

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May combine two claims.

A recent report described the vanA gene cluster harbored in a highly transferable staphylococcal plasmid originally identified in community-associated S. aureus isolates, in a bloodstream MRSA isolate from a Brazilian patient, with transfer to a methicillin-susceptible isolate within the same patient documented.

“Indeed, a recent report described such phenomenon where the vanA gene cluster was harbored in a highly transferable staphylococcal plasmid originally identified in community-associated S. aureus isolates. The isolate was found in a bloodstream isolate of MRSA recovered from a Brazilian patient (80) and transfer to a methicillin-susceptible isolate within the same patient was also documented.”

• cites [80] Rossi F Diaz L Wollam A Panesso D Zhou Y Rincon S Narechania A Xing G Di Gioia TS Doi A Tran TT Reyes J Munita JM Carvajal LP Hernandez-Roldan A Brandão D van der Heijden IM Murray BE Planet PJ Weinstock GM Arias CA Transferable vancomycin resistance in a community-associated MRSA lineage N Engl J Med 2014 370 16 1524 31 24738669 PMC4112484 sourceNot checked yet

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May combine two claims.

Unlike beta-lactams, glycopeptides do not directly interact with PBPs; they bind terminal D-Ala-D-Ala of the pentapeptide moiety of nascent peptidoglycan precursors, preventing PBP-mediated cross-linking and inhibiting cell wall synthesis.

“However, unlike β-lactams, glycopeptides do not directly interact with PBPs. Instead, they bind to the terminal D-alanine-D-alanine (D-Ala-D-Ala) of the pentapeptide moiety of the nascent peptidoglycan precursors (lipid II), preventing PBP-mediated cross-linking and resulting in inhibition of cell wall synthesis.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Development of resistance to daptomycin and vancomycin, the latter at low level in S. aureus, are the most clinically relevant examples of resistance phenotypes resulting from a global cell adaptive response to antibacterial attack.

“Development of resistance to daptomycin (DAP) and vancomycin (low-level in S. aureus) are the most clinically relevant examples of resistance phenotypes that are the result of a global cell adaptive response to the antibacterial attack.”

May combine two claims.

Enterococci can use another bypass strategy by incorporating exogenous tetrahydrofolic acid and folinic acid when these are added to the media, and this ability is correlated with up to a 25-fold increase in TMP-SMX MICs and is thought to impair antimicrobial activity in vivo.

“Interestingly, enterococci use another “bypass” strategy by incorporating exogenous tetrahydrofolic acid and folinic acid when added to the media. This ability to use folate from different sources is correlated with up to 25-fold increase in the MICs of TMP-SMX and are thought to impair the antimicrobial activity in vivo (84, 85).”

• cites [84] Hamilton-Miller JM Reversal of activity of trimethoprim against Gram-positive cocci by thymidine, thymine and ‘folates’ J Antimicrob Chemother 1988 22 35 9 3170389 sourceNot checked yet

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• cites [85] Zervos MJ Schaberg DR Reversal of the in vitro susceptibility of enterococci to trimethoprim – sulfamethoxazole by folinic acid Antimicrob Agents Chemother 1985 28 446 8 3935044 PMC180272 sourceNot checked yet

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May combine two claims.

The vanADLM clusters synthesize precursors ending in D-Lac, whereas the vanCEGN clusters produce D-Ser-ending peptidoglycan.

“The vanADLM clusters synthesize precursors ending in D-Lac whereas the vanCEGN produce D-Ser-ending peptidoglycan.”

May combine two claims.

Most clinical VRE isolates carry the vanA or vanB gene clusters, which are usually found in MGEs associated with plasmids or inserted in the chromosome.

“Most clinical VRE isolates carry the vanA or vanB gene clusters, which are usually found in MGEs either associated with plasmids or inserted in the chromosome.”

May combine two claims.

Community-associated MRSA strains appear to harbor shorter SCCmec cassettes such as type IV and carry fewer antibiotic resistance determinants, whereas hospital-associated isolates possess longer elements such as type II and are usually multidrug resistant.

“Indeed, community-associated MRSA strains appear to harbor shorter SCCmec cassettes (e.g SCCmec type IV) and carry less antibiotic resistance determinants, whereas hospital-associated (HA) isolates possess longer elements (e.g. SCCmec type II) and are usually multidrug resistant (70).”

• cites [70] Chambers HF Deleo FR Waves of resistance: Staphylococcus aureus in the antibiotic era Nat Rev Microbiol 2009 7 9 629 41 19680247 PMC2871281 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The prototypical gene cluster responsible for low-level vancomycin resistance and production of D-Ala-D-Ser peptidoglycan precursors is vanC.

“The prototypical gene cluster responsible for low-level vancomycin resistance and the production of D-Ala-D-Ser peptidoglycan precursors is vanC.”

May combine two claims.

Development of high-level vancomycin resistance in S. aureus, VRSA, was first described in 2002 and resulted from acquisition by an MRSA strain of the vanA gene cluster from a VRE E. faecalis isolate.

“Development of high-level vancomycin resistance in S. aureus (vancomycin-resistant S. aureus, VRSA) was first described in 2002 and was the result of acquisition by an MRSA strain of the vanA gene cluster from a VRE (E. faecalis) isolate (79).”

• cites [79] Sievert DM Rudrik JT Patel JB McDonald LC Wilkins MJ Hageman JC Vancomycin-resistant Staphylococcus aureus in the United States, 2002–2006 Clin Infect Dis 2008 46 5 668 74 18257700 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Acquisition of mecA renders most beta-lactams useless against MRSA, and alternative therapies need to be used in serious infections.

“Acquisition of mecA renders most β-lactams useless against MRSA and alternative therapies need to be used in serious infections.”

May combine two claims.

Changing D-Ala for D-Ser does not remove any of the five hydrogen bonds between vancomycin and its target, but the serine hydroxyl group reduces affinity less markedly than the D-Lac replacement.

“Although the change of D-Ala for D-Ser does not remove any of the 5 hydrogen bonds between vancomycin and its target, the presence of the hydroxyl group of serine affects the interaction of the antibiotic with the precursors reducing its affinity, albeit less markedly than with the D-Lac replacement (74).”

• cites [74] Miller WR Munita JM Arias CA Mechanisms of antibiotic resistance in enterococci Expert Rev Anti Infect Ther 2014 10 12 10 1221 36 25199988 PMC4433168 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

vanX encodes a D,D-dipeptidase that hydrolyzes D-Ala-D-Ala produced in the normal peptidoglycan synthesis pathway, and vanY encodes a membrane-bound D,D-carboxypeptidase that removes the last D-Ala of normal ending precursors, ensuring no D-Ala-D-Ala-ending pentapeptides are exposed on the cell surface.

“The vanX gene encodes a D,D-dipeptidase that hydrolyzes any D-Ala-D-Ala produced in the “normal” peptidoglycan synthesis pathway and vanY codes for a membrane-bound D,D-carboxypeptidase that removes the last D-Ala of normal ending precursors, ensuring that no D-Ala-D-Ala-ending pentapeptides (that could potentially bind vancomycin) are exposed on the cell surface.”

May combine two claims.

vanZ appears to be involved in teicoplanin resistance but not vancomycin resistance, and its function is unknown.

“Finally, Tn1546 harbors another gene (designated vanZ) that appears to be involved in teicoplanin resistance (but not vancomycin) whose function is unknown (76).”

• cites [76] Courvalin P Vancomycin resistance in gram-positive cocci Clin Infect Dis 2006 42 S25 34 16323116 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These changes were sufficient to abolish the in vitro bactericidal activity of DAP and were associated with a clinical failure in a neutropenic patient with VRE bacteremia.

“More importantly, these changes were sufficient to abolish the in vitro bactericidal activity of DAP and were associated with a clinical failure in a neutropenic patient with VRE bacteremia (92).”

• cites [92] Munita JM Mishra NN Alvarez D Tran TT Diaz L Panesso D Reyes J Murray BE Adachi JA Bayer AS Arias CA Failure of high-dose daptomycin for bacteremia caused by daptomycin-susceptible Enterococcus faecium harboring LiaSR substitutions Clin Infect Dis 2014 59 9 1277 80 25107294 PMC4271039 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In B. subtilis, the lia locus consists of six genes, liaIH-liaGFSR, of which liaGFSR are constitutively expressed at a low basal level due to a weak constitutive promoter upstream of liaG.

“In B. subtilis, the lia locus consists of six genes, liaIH-liaGFSR, of which liaGFSR are constitutively expressed at a low basal level due to the presence of a weak constitutive promoter upstream of liaG.”

• cites [93] Wolf D Kalamorz F Wecke T Juszczak A Mäder U Homuth G Jordan S Kirstein J Hoppert M Voigt B Hecker M Mascher T In-depth profiling of the LiaR response of Bacillus subtilis J Bacteriol 2010 9 192 18 4680 93 20639339 PMC2937411 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A single deletion of an isoleucine at position 177 of LiaF increased the DAP MIC from 1 to 4 μg/mL and was sufficient to abolish the bactericidal activity of DAP.

“Indeed, a single deletion of an isoleucine at position 177 of LiaF increased the DAP MIC from 1 to 4 μg/mL (established clinical breakpoint is 4 μg/ml) and, more importantly, was sufficient to abolish the bactericidal activity of DAP (89).”

• cites [89] Munita JM Tran TT Diaz L Panesso D Reyes J Murray BE Arias CA A liaF codon deletion abolishes daptomycin bactericidal activity against vancomycin-resistant Enterococcus faecalis Antimicrob Agents Chemother 2013 6 57 6 2831 3 23507277 PMC3716119 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

VanC-type resistance differs from VanA and VanB by encoding a unique racemase VanT that produces D-serine from L-serine, possessing a ligase that synthesizes D-Ala-D-Ser dipeptides, and often harboring a single vanXY gene encoding both D-Ala-D-Ala dipeptidase and carboxypeptidase activities.

“The main differences in terms of gene content and biochemical activities of VanC-type mediated resistance compared with VanA and VanB are, i) they encode a unique racemase (VanT) capable of producing D-serine using L-serine as substrate, ii) they possess a ligase (vanCEGLN) with the ability to synthesize a D-Ala-D-Ser dipeptides, and iii) they often harbor a single gene (vanXY) encoding both D-Ala”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The vanA gene cluster is usually located on the Tn3-family transposon Tn1546, which has been found on both conjugative and non-conjugative plasmids.

“The vanA gene cluster is usually located on a Tn3-family transposon designated Tn1546, which has been found on both conjugative and non-conjugative plasmids.”

May combine two claims.

TMP-SMX impairs bacterial synthesis of purines and some important amino acids by altering folate production, exploiting the fact that most bacteria cannot incorporate folate from external sources.

“This drug impairs bacterial synthesis of purines and some important amino acids by altering the production of folate, exploiting the fact that most bacteria are unable to incorporate folate from external sources.”

May combine two claims.

Vancomycin resistance is especially relevant in enterococci, particularly E. faecium, and is usually accompanied by other resistance determinants, making treatment of infections caused by these organisms an important clinical challenge.

“Vancomycin resistance is especially relevant in enterococci (particularly E. faecium) and it is usually accompanied by the presence of other resistance determinants, making the treatment of infections caused by these organisms an important clinical challenge (73).”

• cites [73] Arias CA Murray BE The rise of the Enterococcus: beyond vancomycin resistance Nat Rev Microbiol 2012 10 266 78 22421879 PMC3621121 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

This initial step results in ATP-dependent phosphorylation of VanR, which subsequently binds to two promoters, one upstream of vanR and the other upstream of vanH in Tn1546.

“This initial step results in an ATP-dependent phosphorylation of the response regulator VanR, which subsequently binds to two promoters, one of them located upstream of its own gene (vanR) and the other upstream of vanH in Tn1546 (78).”

• cites [78] Arthur M Molinas C Courvalin P The VanS-VanR two-component regulatory system controls synthesis of depsipeptide peptidoglycan precursors in Enterococcus faecium BM4147 J Bacteriol 1992 4 174 8 2582 91 1556077 PMC205897 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The folate synthetic pathway involves DHPS, which forms dihydrofolate from para-aminobenzoic acid and is inhibited by SMX, and DHFR, which catalyzes formation of tetrahydrofolate from dihydrofolate and is inhibited by TMP.

“The synthetic pathway of folate involves two major enzymes, namely i) dihydropteroic acid synthase (DHPS), which forms dihydrofolate from para-aminobenzoic acid (inhibited by SMX), and ii) dihydrofolate reductase (DHFR), which catalyzes the formation of tetrahydrofolate from dihydrofolate (inhibited by TMP).”

May combine two claims.

The vanB gene cluster harbors genes similar to those of the vanA cluster, with the difference that the VanSB sensor kinase does not appear to be activated by teicoplanin.

“The vanB gene cluster harbor similar genes to those carried by the vanA cluster with the difference that the VanSB sensor kinase does not appear to be activated by the presence of teicoplanin.”

May combine two claims.

Cardiolipin (CL) seems to play an important role in the translocation of DAP oligomers from the outer to the inner leaflet, but its contribution is not completely understood.

“Additionally, another phospholipid (cardiolipin, CL), seems to play an important role in the translocation of DAP oligomers from the outer of the inner leaflet, but its contribution is not completely understood.”

• cites [87] Zhang T Muraih JK Tishbi N Herskowitz J Victor RL Silverman J Uwumarenogie S Taylor SD Palmer M Mintzer E Cardiolipin prevents membrane translocation and permeabilization by daptomycin J Biol Chem 2014 4 25 289 17 11584 91 24616102 PMC4002069 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Enterococci carrying the vanEGLN clusters also produce D-Ala-D-Ser, exhibit low-level vancomycin resistance, and carry genes similar to those described in vanC.

“Of note, enterococci carrying the vanEGLN clusters also produce D-Ala-D-Ser and exhibit low level of vancomycin resistance and carry similar genes to those described in vanC.”

May combine two claims.

MprF harbors two domains: a lysyl-transferase domain that transfers lysine from its tRNA carrier to PG (LPG) in the inner leaflet of the CM, and a flipase domain that translocates newly synthesized LPG from the inner to the outer leaflet of the CM.

“This enzyme harbors two domains, i) a lysyl-transferase domain that transfers the positively-charged amino acid lysine from its tRNA carrier to PG (LPG) in the inner leaflet of the CM, and ii) a flipase domain, through which newly synthesized LPG is translocated from the inner to the outer leaflet of the CM (99).”

• cites [99] Ernst CM Kuhn S Slavetinsky CJ Krismer B Heilbronner S Gekeler C Kraus D Wagner S Peschel A The lipid-modifying multiple peptide resistance factor is an oligomer consisting of distinct interacting synthase and flippase subunits MBio 2015 6 1 pii: e02340-14 PMC4324311 25626904 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In S. aureus, MprF (a lysyl-PG [LPG] synthase) has been one of the most studied enzymes, and inactivation of this protein reversed DAP-R.

“In S. aureus, MprF (a lysyl-PG [LPG] synthase) has been one of the most studied enzymes, and inactivation of this protein reversed DAP-R.”

• cites [99] Ernst CM Kuhn S Slavetinsky CJ Krismer B Heilbronner S Gekeler C Kraus D Wagner S Peschel A The lipid-modifying multiple peptide resistance factor is an oligomer consisting of distinct interacting synthase and flippase subunits MBio 2015 6 1 pii: e02340-14 PMC4324311 25626904 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Mutations in mprF appear to produce a gain of function of the enzyme, and as a result the cell surface becomes more positively charged, repelling the DAP-calcium complex.

“Mutations in mprF appear to produce a gain of function of the enzyme and, as a result, the cell surface becomes more positively charged, repelling the DAP-calcium complex (also with positive charge).”

May combine two claims.

Phenotypically, hVISA/VISA strains exhibit distinct metabolic characteristics that may include increased fructose utilization, increased fatty acid metabolism, impaired acetate metabolism and tricarboxylic acid cycle, decreased glutamate availability, and increased expression of cell wall synthesis genes.

“Phenotypically, hVISA/VISA strains exhibit distinct metabolic characteristics that may include i) increase in fructose utilization, ii) increased fatty acid metabolism, iii) impaired acetate metabolism and tricarboxylic acid cycle, iv) decrease in glutamate availability, and iv) increase expression of cell wall synthesis genes.”

• cites [101] Howden BP Davies JK Johnson PD Stinear TP Grayson ML Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications Clin Microbiol Rev 2010 1 23 1 99 139 20065327 PMC2806658 sourceNot checked yet

  Not checked in the free run.

• cites [104] Gardete S Tomasz A Mechanisms of vancomycin resistance in Staphylococcus aureus J Clin Invest 2014 124 7 2836 40 24983424 PMC4071404 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

LiaI is a small hydrophobic protein of unknown function with two putative transmembrane helices and LiaH is a member of the phage-shock protein family that forms large oligomeric rings-like structures.

“LiaI is a small hydrophobic protein of unknown function with two putative transmembrane helices and LiaH is a member of the phage-shock protein family that forms large oligomeric rings-like structures (resembling what has been reported with PspA in E. coli).”

• cites [93] Wolf D Kalamorz F Wecke T Juszczak A Mäder U Homuth G Jordan S Kirstein J Hoppert M Voigt B Hecker M Mascher T In-depth profiling of the LiaR response of Bacillus subtilis J Bacteriol 2010 9 192 18 4680 93 20639339 PMC2937411 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Deletion of LiaR completely reverted DAP susceptibility and restored the organization of CL domains.

“Furthermore, deletion of LiaR completely reverted DAP susceptibility and restored the organization of CL domains (95).”

• cites [95] Reyes J Panesso D Tran TT Mishra NN Cruz MR Munita JM Singh KV Yeaman MR Murray BE Shamoo Y Garsin D Bayer AS Arias CA A liaR Deletion Restores Susceptibility to Daptomycin and Antimicrobial Peptides in Multidrug-Resistant Enterococcus faecalis J Infect Dis 2014 10 31 pii: jiu602 PMC4402337 25362197 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These two- and three-component regulatory systems are involved in cell wall homeostasis, supporting the notion that selection of the hVISA/VISA phenotype involves important remodeling of the cell wall in order to survive the antimicrobial attack.

“Interestingly, these two- and three component regulatory systems are involved in cell wall homeostasis, supporting the notion that selection of the hVISA/VISA phenotype involves important remodeling of the cell wall in order to survive the antimicrobial attack.”

May combine two claims.

The VISA phenomenon was first reported in Japan in 1997 and led to therapeutic failure.

“This phenomenon was first reported in Japan in 1997 and led to therapeutic failure (100).”

• cites [100] Hiramatsu K Hanaki H Ino T Yabuta K Oguri T Tenover FC Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility J Antimicrob Chemother 1997 7 40 1 135 6 9249217 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Detection of hVISA is very challenging, and some S. aureus strains reported as susceptible to vancomycin by standard susceptibility testing may still exhibit this phenotype.

“As the “resistant” subpopulation is difficult to identify, detection of hVISA becomes very challenging and some S. aureus strains reported as “susceptible” to vancomycin by standard susceptibility testing may still exhibit this phenotype (101).”

• cites [101] Howden BP Davies JK Johnson PD Stinear TP Grayson ML Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications Clin Microbiol Rev 2010 1 23 1 99 139 20065327 PMC2806658 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These changes are postulated to result in trapping of vancomycin in outer layers of the peptidoglycan, preventing the antibiotic from reaching its target of precursors emerging from the cytoplasmic membrane, so that cell wall synthesis and peptidoglycan cross-linking continue uninterrupted.

“Hence, it has been postulated that these changes result in “trapping” of vancomycin in outer layers of the peptidoglycan preventing the antibiotic molecule from reaching its target of precursors emerging from the cytoplasmic membrane. As a result, cell wall synthesis and peptidoglycan cross-linking continues to be uninterrupted.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Published studies estimate that the overall prevalence of MRSA strains with hVISA/VISA profile ranges between 0 and 8.24%, but it can be as high as 30% in selected populations (e.g. patients with MRSA infective endocarditis).

“Published studies estimate that the overall prevalence of MRSA strains with hVISA/VISA profile range between 0 and 8.24%, but it can be as high as 30% in selected populations (e.g. patients with MRSA infective endocarditis) (102, 103).”

• cites [102] Stryjewski ME Corey GR Methicillin-resistant Staphylococcus aureus: an evolving pathogen Clin Infect Dis 2014 1 58 Suppl 1 S10 9 24343827 sourceNot checked yet

  Not checked in the free run.

• cites [103] Bae IG Federspiel JJ Miró JM Woods CW Park L Rybak MJ Rude TH Bradley S Bukovski S de la Maria CG Kanj SS Korman TM Marco F Murdoch DR Plesiat P Rodriguez-Creixems M Reinbott P Steed L Tattevin P Tripodi MF Newton KL Corey GR Fowler VG Jr International Collaboration on Endocarditis-Microbiology Investigator Heterogeneous vancomycin-intermediate susceptibility phenotype in bloodstream methicillin-resistant Staphylococcus aureus isolates from an international cohort of patients with infective endocarditis: prevalence, genotype, and clinical significance J Infect Dis 2009 200 9 1355 66 19811099 P sourceNot checked yet

  Not checked in the free run.

May combine two claims.

VISA strains bind vancomycin more avidly than their non-VISA counterparts, but diffusion of the antibiotic molecule into the inner part of the cell wall appears to be impaired.

“In addition, VISA strains bind vancomycin more avidly than their non –VISA counterparts, however, diffusion of the antibiotic molecule into the inner part of the cell wall appears to be impaired.”

• cites [101] Howden BP Davies JK Johnson PD Stinear TP Grayson ML Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications Clin Microbiol Rev 2010 1 23 1 99 139 20065327 PMC2806658 sourceNot checked yet

  Not checked in the free run.

• cites [104] Gardete S Tomasz A Mechanisms of vancomycin resistance in Staphylococcus aureus J Clin Invest 2014 124 7 2836 40 24983424 PMC4071404 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These global homeostatic changes appear to lead to reduced autolytic activity with thickened cell wall and an increased amount of free D-Ala-D-Ala dipeptides with less peptidoglycan cross-linking.

“These global homeostatic changes appear to lead to a reduced autolytic activity with thickened cell wall and an increase amount of free D-Ala-D-Ala dipeptides with less peptidoglycan cross-linking (101, 104).”

• cites [101] Howden BP Davies JK Johnson PD Stinear TP Grayson ML Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications Clin Microbiol Rev 2010 1 23 1 99 139 20065327 PMC2806658 sourceNot checked yet

  Not checked in the free run.

• cites [104] Gardete S Tomasz A Mechanisms of vancomycin resistance in Staphylococcus aureus J Clin Invest 2014 124 7 2836 40 24983424 PMC4071404 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

There seems to be a price to pay for developing resistance, and this is yet another example of the ability of bacteria to adapt to the environment by means of their remarkable genetic plasticity.

“Therefore, there seems to be a “price” to pay for developing resistance and this is yet another example of the ability of bacteria to adapt to the environment by means of their remarkable genetic plasticity.”