Antibiotic tolerance

Westblade, Lars F.; Errington, Jeff; Dörr, Tobias

doi:10.1371/journal.ppat.1008892

Cited by 53 publications

(46 citation statements)

References 46 publications

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“…Despite being a well-known regulator of polymyxin resistance, the PhoPQ two-component system was not previously known to respond or mediate tolerance to carbapenem treatment. As tolerance (and spheroplast formation in particular) is a possible culprit for antibiotic treatment failure (2, 3, 43), our results suggest a potential for combination therapies with histidine kinase inhibitors to increase the efficacy of carbapenems.…”

Section: Discussionmentioning

confidence: 80%

“…However, the response to an antibiotic is oftentimes more nuanced than a simple dichotomy of resistance vs. susceptibility. Bacteria can survive treatment in a non- or slowly-proliferating state, readily reverting to healthy growth after removal of the antibiotic (such as the end of a treatment course), and this is typically referred to as “antibiotic tolerance” (1-3). Importantly, tolerance to antibotics has been shown to enhance the evolution of outright resistance mechanisms (4-6), and can thus serve as both a direct and indirect contributor to treatment failure.…”

Section: Introductionmentioning

confidence: 99%

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High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications

Murtha

Kazi

Schargel

et al. 2021

Preprint

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Antibiotic tolerance is an understudied potential contributor to antibiotic treatment failure and the emergence of multidrug-resistant bacteria. The molecular mechanisms governing tolerance remain poorly understood. A prominent type of β-lactam tolerance relies on the formation of cell wall-deficient spheroplasts, which maintain structural integrity via their outer membrane (OM), an asymmetric lipid bilayer consisting of phospholipids on the inner leaflet and a lipid-linked polysaccharide (lipopolysaccharide, LPS) enriched in the outer monolayer on the cell surface. How a membrane structure like LPS, with its reliance on mere electrostatic interactions to maintain stability, is capable of countering internal turgor pressure is unknown. Here, we have uncovered a novel role for the PhoPQ two-component system in tolerance to the β-lactam antibiotic meropenem in Enterobacterales. We found that PhoPQ is induced by meropenem treatment and promotes an increase in 4-amino-4-deoxy-L-aminoarabinose [L-Ara4N] modification of lipid A, the membrane anchor of LPS. L-Ara4N modifications enhance structural integrity, and consequently tolerance to meropenem, in several Enterobacterales species. Importantly, mutational inactivation of the negative PhoPQ regulatory element mgrB (commonly selected for during clinical therapy with the last-resort antibiotic colistin, an antimicrobial peptide [AMP]) results in dramatically enhanced tolerance, suggesting that AMPs can collaterally select for meropenem tolerance via stable overactivation of PhoPQ. Lastly, we identify histidine kinase inhibitors (including an FDA-approved drug) that inhibit PhoPQ-dependent LPS modifications and consequently potentiate meropenem to enhance killing of tolerant cells. In summary, our results suggest that PhoPQ-mediated LPS modifications play a significant role in stabilizing the OM, promoting survival when the primary integrity maintenance structure, the cell wall, is removed.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications

Murtha

Kazi

Schargel

et al. 2021

Preprint

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“…We chose to model the protection hypothesis because several mechanisms are known that can produce this effect [12]. One is for cells to enter a 'tolerant' or 'persister' state, analogous to known mechanisms of antibiotic tolerance [19] involving either physiological changes (such as cell wall reduction or loss) or a reduction in metabolic rate (dormancy [20]). A second is for pathogens to invade some tissue that is protected from the host immune response.…”

Section: Chronic Infection and Protected Pathogensmentioning

confidence: 99%

Host–pathogen immune feedbacks can explain widely divergent outcomes from similar infections

et al. 2021

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A long-standing question in infection biology is why two very similar individuals, with very similar pathogen exposures, may have very different outcomes. Recent experiments have found that even isogenic Drosophila melanogaster hosts, given identical inoculations of some bacterial pathogens at suitable doses, can experience very similar initial bacteria proliferation but then diverge to either a lethal infection or a sustained chronic infection with much lower pathogen load. We hypothesized that divergent infection outcomes are a natural result of mutual negative feedbacks between pathogens and the host immune response. Here, we test this hypothesis in silico by constructing process-based dynamic models for bacterial population growth, host immune induction and the feedbacks between them, based on common mechanisms of immune system response. Mathematical analysis of a minimal conceptual model confirms our qualitative hypothesis that mutual negative feedbacks can magnify small differences among hosts into life-or-death differences in outcome. However, explaining observed features of chronic infections requires an extension of the model to include induced pathogen modifications that shield themselves from host immune responses at the cost of reduced proliferation rate. Our analysis thus generates new, testable predictions about the mechanisms underlying bimodal infection outcomes.

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“…Several mechanisms are known that can produce this effect [12]. One is for cells to enter a "tolerant" or "persister" state, analogous to known mechanisms of antibiotic tolerance [2] involving either physiological changes (such as cell wall reduction or loss) or a reduction in metabolic rate (dormancy, Westblade et al [22]). A second is for pathogens to invade some tissue that is protected from the host immune response.…”

Section: Chronic Infection and Protected Pathogensmentioning

confidence: 99%

Host-pathogen Immune Feedbacks Can Explain Widely Divergent Outcomes from Similar Infections

Ellner

Buchon

Dörr

et al. 2021

Preprint

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A longstanding question in infection biology is why two very similar individuals, with very similar pathogen exposures, may have very different outcomes. Recent experiments have found that even isogenic Drosophila melanogaster hosts, given identical inoculations of some bacterial pathogens at suitable doses, can experience very similar initial bacteria proliferation but then diverge to either a lethal infection or a sustained chronic infection with much lower pathogen load. We hypothesized that divergent infection outcomes are a natural result of mutual negative feedbacks between pathogens and the host immune response. Here we test this hypothesis in silico by constructing process-based dynamic models for bacterial population growth, host immune induction, and the feedbacks between them, based on common mechanisms of immune system response. Mathematical analysis of a minimal conceptual model confirms our qualitative hypothesis that mutual negative feedbacks can magnify small differences among hosts into life-or-death differences in outcome. However, explaining observed features of chronic infections requires an extension of the model to include induced pathogen modifications that shield themselves from host immune responses at the cost of reduced proliferation rate. Our analysis thus generates new, testable predictions about the mechanisms underlying bimodal infection outcomes.

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Antibiotic tolerance

Cited by 53 publications

References 46 publications

High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications

High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications

Host–pathogen immune feedbacks can explain widely divergent outcomes from similar infections

Host-pathogen Immune Feedbacks Can Explain Widely Divergent Outcomes from Similar Infections

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