Mechanisms of Antibiotic Resistance

In the paper

“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).”

What the sources say

• Not checked yetcites [39] Nikaido H Molecular basis of bacterial outer membrane permeability revisited Microbiol Mol Biol Rev 2003 12 67 4 593 656 14665678 PMC309051 source

In the paper

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

In the paper

“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).”

In the paper

“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.”

What the sources say

• Not checked yetcites [39] Nikaido H Molecular basis of bacterial outer membrane permeability revisited Microbiol Mol Biol Rev 2003 12 67 4 593 656 14665678 PMC309051 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [13] Hollenbeck BL Rice LB Intrinsic and acquired resistance mechanisms in enterococcus Virulence 2012 8 15 3 5 421 33 23076243 PMC3485979 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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, 2015

In the paper

“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).”

What the sources say

• Not checked yetcites [19] Bush K The ABCD’s of β-lactamase nomenclature J Infect Chemother 2013 8 19 4 549 59 23828655 source
• Not checked yetcites [20] Bush K Jacoby GA 2010 Updated functional classification of β-Lactamases Antimicrob Agents Chemother 54 969 976 19995920 PMC2825993 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source
• Not checked yetcites [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 source
• Not checked yetcites [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 source

In the paper

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

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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 source

In the paper

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

In the paper

“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.”

In the paper

“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”).”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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, 2015

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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, 2015

In the paper

“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).”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [58] Floss HG Yu TW Rifamycin-mode of action, resistance, and biosynthesis Chem Rev 2005 2 105 2 621 32 15700959 source

In the paper

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

What the sources say

• Not checked yetcites [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 source
• Not checked yetcites [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 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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).”

What the sources say

• Not checked yetcites [44] Poole K Efflux-mediated antimicrobial resistance J Antimicrob Chemother 2005 7 56 1 20 51 15914491 source
• Not checked yetcites [47] Roberts MC Update on acquired tetracycline resistance genes FEMS Microbiol Lett 2005 4 15 245 2 195 203 15837373 source

In the paper

“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).”

What the sources say

• Not checked yetcites [59] Hooper DC Fluoroquinolone resistance among Gram-positive cocci Lancet Infect Dis 2002 9 2 9 530 8 12206969 source

In the paper

“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).”

In the paper

“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).”

What the sources say

• Not checked yetcites Du D Nature 2014

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [44] Poole K Efflux-mediated antimicrobial resistance J Antimicrob Chemother 2005 7 56 1 20 51 15914491 source

In the paper

“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).”

What the sources say

• Not checked yetcites [46] Piddock LJ Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria Clin Microbiol Rev 2006 4 19 2 382 402 16614254 PMC1471989 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 source

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source
• Not checked yetcites [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 source

In the paper

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

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [70] Chambers HF Deleo FR Waves of resistance: Staphylococcus aureus in the antibiotic era Nat Rev Microbiol 2009 7 9 629 41 19680247 PMC2871281 source

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [76] Courvalin P Vancomycin resistance in gram-positive cocci Clin Infect Dis 2006 42 S25 34 16323116 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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”

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [73] Arias CA Murray BE The rise of the Enterococcus: beyond vancomycin resistance Nat Rev Microbiol 2012 10 266 78 22421879 PMC3621121 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 source

In the paper

“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).”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 source
• Not checked yetcites [104] Gardete S Tomasz A Mechanisms of vancomycin resistance in Staphylococcus aureus J Clin Invest 2014 124 7 2836 40 24983424 PMC4071404 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

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

What the sources say

• Not checked yetcites [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 source

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [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 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [102] Stryjewski ME Corey GR Methicillin-resistant Staphylococcus aureus: an evolving pathogen Clin Infect Dis 2014 1 58 Suppl 1 S10 9 24343827 source
• Not checked yetcites [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 source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 source
• Not checked yetcites [104] Gardete S Tomasz A Mechanisms of vancomycin resistance in Staphylococcus aureus J Clin Invest 2014 124 7 2836 40 24983424 PMC4071404 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 source
• Not checked yetcites [104] Gardete S Tomasz A Mechanisms of vancomycin resistance in Staphylococcus aureus J Clin Invest 2014 124 7 2836 40 24983424 PMC4071404 source

In the paper

“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.”