Slow growth of M ycobacterium tuberculosis at acidic pH is regulated by phoPR and host‐associated carbon sources

Baker, Jacob J.; Johnson, Benjamin K.; Abramovitch, Robert B.

doi:10.1111/mmi.12688

Cited by 181Tuberculosis Research and EpidemiologyBacterial Genetics and BiotechnologyMycobacterium research and diagnosis

Slow growth of M ycobacterium tuberculosis at acidic pH is regulated by phoPR and host‐associated carbon sources

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Baker, Jacob J., Johnson, Benjamin K., Abramovitch, Robert B.·2014·Molecular Microbiology

DOI 10.1111/mmi.12688PMC PMC4177513

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Abstract

Summary: During pathogenesis, M ycobacterium tuberculosis ( Mtb ) colonizes environments, such as the macrophage or necrotic granuloma, that are acidic and rich in cholesterol and fatty acids. The goal of this study was to examine how acidic pH and available carbon sources interact to regulate Mtb physiology. Here we report that Mtb growth at acidic pH requires host‐associated carbon sources that function at the intersection of glycolysis and the TCA cycle, such as pyruvate, acetate, oxaloacetate and cholesterol. In contrast, in other tested carbon sources, Mtb fully arrests its growth at acidic pH and establishes a state of non‐replicating persistence. Growth‐arrested Mtb is resuscitated by the addition of pyruvate suggesting that growth arrest is due to a pH ‐dependent checkpoint on metabolism. Additionally, we demonstrate that the phoPR two‐component regulatory system is required to slow Mtb growth at acidic pH and functions to maintain redox homeostasis. Transcriptional profiling and functional metabolic studies demonstrate that signals from acidic pH and carbon source are integrated to remodel pathways associated with anaplerotic central metabolism, lipid anabolism and the regeneration of oxidized cofactors. Because phoPR is required for Mtb virulence in animals, we suggest that pH ‐driven adaptation may be critical to Mtb pathogenesis.

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Acidification of the phagolysosome decreases mycobacterial metabolism, which becomes highly dependent on the availability of specific carbon sources such as pyruvate, acetate, or cholesterol, otherwise resulting in growth arrest.
“Of note, acidification of the phagolysosome decreases mycobacterial metabolism, which becomes highly dependent on the availability of specific carbon sources such as pyruvate, acetate, or cholesterol, otherwise resulting in growth arrest (48).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [48]
M. tuberculosis can survive at pH of 4.5, which has been linked to the expression of a specific resistance gene named Rv3671c.
“However, M. tuberculosis can survive at pH of 4.5, which has been linked to the expression of a specific resistance gene named Rv3671c (47, 48).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [48]

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Mycobacterium tuberculosis protease MarP activates a peptidoglycan hydrolase during acid stress
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Inhibiting Mycobacterium tuberculosis DosRST Signaling by Targeting Response Regulator DNA Binding and Sensor Kinase Heme
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Types and functions of heterogeneity in mycobacteria
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Mycobacterium tuberculosis PPE51 Inhibits Autophagy by Suppressing Toll-Like Receptor 2-Dependent Signaling
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Understanding the contribution of metabolism to Mycobacterium tuberculosis drug tolerance
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EspR, a regulator of the ESX-1 secretion system in Mycobacterium tuberculosis, is directly regulated by the two-component systems MprAB and PhoPR
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HC2091 Kills Mycobacterium tuberculosis by Targeting the MmpL3 Mycolic Acid Transporter
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MTS1338, A Small Mycobacterium tuberculosis RNA, Regulates Transcriptional Shifts Consistent With Bacterial Adaptation for Entering Into Dormancy and Survival Within Host Macrophages
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EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System
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Pyrazinamide Is Active against Mycobacterium tuberculosis Cultures at Neutral pH and Low Temperature
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Inhibiting DosRST As a New Approach to Tuberculosis Therapy
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Identification of bacterial determinants of tuberculosis infection and treatment outcomes: a phenogenomic analysis of clinical strains
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TcrXY is an acid-sensing two-component transcriptional regulator of Mycobacterium tuberculosis required for persistent infection
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Comparing the Metabolic Capabilities of Bacteria in the Mycobacterium tuberculosis Complex
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Mycobacterium tuberculosis Reporter Strains as Tools for Drug Discovery and Development
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Expression of the Genes Encoding the Trk and Kdp Potassium Transport Systems ofMycobacterium tuberculosisduring GrowthIn Vitro
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Deciphering the Proteomic Landscape of Mycobacterium tuberculosis in Response to Acid and Oxidative Stresses
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PrrA modulates Mycobacterium tuberculosis response to multiple environmental cues and is critically regulated by serine/threonine protein kinases
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ppe51 Variants Enable Growth of Mycobacterium tuberculosis at Acidic pH by Selectively Promoting Glycerol Uptake
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Anaerobic Mycobacterium tuberculosis Cell Death Stems from Intracellular Acidification Mitigated by the DosR Regulon
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Identification of host regulators of Mycobacterium tuberculosis phenotypes uncovers a role for the MMGT1-GPR156 lipid droplet axis in persistence
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Flavin Storage and Sequestration by Mycobacterium tuberculosis Dodecin
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Molecular Connectivity between Extracytoplasmic Sigma Factors and PhoP Accounts for Coupled Mycobacterial Stress Response
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Characterization of the two component regulatory system PhoPR in Mycobacterium bovis
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Mycobacterium tuberculosis response to cholesterol is integrated with environmental pH and potassium levels via a lipid metabolism regulator
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Unraveling Mycobacterium tuberculosis acid resistance and pH homeostasis mechanisms
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Tetanus Toxin Synthesis is Under the Control of A Complex Network of Regulatory Genes in Clostridium tetani
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Targeting Mycobacterium tuberculosis pH-driven adaptation
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An exacerbated phosphate starvation response triggers Mycobacterium tuberculosis glycerol utilization at acidic pH
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Dynamic interplay of autophagy and membrane repair during Mycobacterium tuberculosis Infection
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Carbon dioxide regulates Mycobacterium tuberculosis PhoPR signaling and virulence
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Genome-Wide Analysis Reveals that PhoP Regulates Pathogenicity in Riemerella anatipestifer
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Role of the Extracytoplasmic Function Sigma Factor SigE in the Stringent Response of Mycobacterium tuberculosis
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Clinically relevant mutations in the PhoR sensor kinase of host-adapted Mycobacterium abscessus isolates impact response to acidic pH and virulence
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Mycobacterium tuberculosis PhoP integrates stress response to intracellular survival by regulating cAMP level
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Revisiting the expression signature of pks15/1 unveils regulatory patterns controlling phenolphtiocerol and phenolglycolipid production in pathogenic mycobacteria
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Phosphate responsive regulation provides insights for ESX-5 function in Mycobacterium tuberculosis
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Structural and Molecular Dynamics of Mycobacterium tuberculosis Malic Enzyme, a Potential Anti-TB Drug Target
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The antagonistic transcription factors, EspM and EspN, regulate the ESX-1 secretion system in M. marinum
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“Genetic regulation of Mycobacterium tuberculosis in a lipid-rich environment”
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Over-expression of Tgs1 in Mycobacterium marinum enhances virulence in adult zebrafish
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Shining a light on bacterial environmental cue integration and its relation to metabolism
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Mechanisms of Salmonella Attachment and Survival on In-Shell Black Peppercorns, Almonds, and Hazelnuts
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AC2P20 selectively kills Mycobacterium tuberculosis at acidic pH by depleting free thiols
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Rv3852 (H-NS) of Mycobacterium tuberculosis Is Not Involved in Nucleoid Compaction and Virulence Regulation
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RNA G-quadruplexes inhibit translation of the PE/PPE transcripts in Mycobacterium tuberculosis
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Unravelling the flexibility of Mycobacterium tuberculosis: an escape way for the bacilli
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Building Optimal Three-Drug Combination Chemotherapy Regimens To Eradicate Mycobacterium tuberculosis in Its Slow-Growth Acid Phase
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Insights into Natural Products from Marine-Derived Fungi with Antimycobacterial Properties: Opportunities and Challenges
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Acid Fasting: Modulation of Mycobacterium tuberculosis Metabolism at Acidic pH
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Mycobacterium tuberculosis growth arrest on propionate at acidic pH is suppressed by mutations in phoPR and pyrazinamide treatment
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Targeting Mycobacterium tuberculosis pH-driven adaptation
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Growth of Mycobacterium tuberculosis at acidic pH depends on lipid assimilation and is accompanied by reduced GAPDH activity
Gouzy, A., Healy, C. M., Black, K. A., Rhee, K. Y., & Ehrt, S. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2024571118 · Cited by 86 · see citing works
Context-dependent acetylation of the virulence regulator PhoP accounts for carbon-source specific intracellular growth program of Mycobacterium tuberculosisPreprint
Paul, P., Mehta, K., Ujjainiya, R., Bamniya, B., Thakur, B., Goar, H., & Sarkar, D. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.25.577197

Authors: Baker, J. J., Johnson, B. K., & Abramovitch, R. B.
Affiliations: Michigan State University (US)
Corresponding author: Abramovitch, Robert B.
ORCID: Baker, Jacob J.
Abramovitch, Robert B.
Venue: Molecular Microbiology
Publisher: Wiley
Published: 2014-07-13
Volume: 94
Issue: 1
Pages: 56-69
ISSN: 0950-382X (ISSN-L)
1365-2958
DOI: 10.1111/mmi.12688
PMC: PMC4177513
OpenAlex: W1905249904
Cited by: 181
References: 61
Citations by year: 2026: 21 · 2025: 22 · 2024: 15 · 2023: 23 · 2022: 21 · 2021: 9 · 2020: 12 · 2019: 15 · 2018: 9 · 2017: 12 · 2016: 9 · 2015: 9 · 2014: 4
FWCI: 7.97
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Molecular Microbiology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (U54AI057153)
Topics: Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
Keywords: Mycobacterium tuberculosis, low pH, pyruvate, cholesterol, growth arrest, non-replicating persistence, redox homeostasis, anaplerotic metabolism, virulence
MeSH terms: Acids, Bacterial Proteins, Carbon, Citric Acid Cycle, Glycolysis, Humans, Hydrogen-Ion Concentration, Mycobacterium tuberculosis, Tuberculosis, Gene Expression Regulation, Bacterial

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Slow growth of M ycobacterium tuberculosis at acidic pH is regulated by phoPR and host‐associated carbon sources

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