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Targeting Phenotypically Tolerant

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  • Authors: Ben Gold1, Carl Nathan2
  • Editors: William R. Jacobs Jr.3, Helen McShane4, Valerie Mizrahi5, Ian M. Orme6
    Affiliations: 1: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065; 2: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065; 3: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 4: University of Oxford, Oxford OX3 7DQ, United Kingdom; 5: University of Cape Town, Rondebosch 7701, South Africa; 6: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec February 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.TBTB2-0031-2016
  • Received 26 September 2016 Accepted 28 October 2016 Published 24 February 2017
  • Ben Gold, [email protected]
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  • Abstract:

    While the immune system is credited with averting tuberculosis in billions of individuals exposed to , the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of . The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in clinical settings. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of posttreatment relapse. Some promising drugs to treat tuberculosis, such as rifampin and bedaquiline, only kill nonreplicating at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating . With this goal, we review methods of high-throughput screening to target nonreplicating and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating revealed a rich diversity in pharmacophores.

  • Citation: Gold B, Nathan C. 2017. Targeting Phenotypically Tolerant . Microbiol Spectrum 5(1):TBTB2-0031-2016. doi:10.1128/microbiolspec.TBTB2-0031-2016.


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While the immune system is credited with averting tuberculosis in billions of individuals exposed to , the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of . The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in clinical settings. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of posttreatment relapse. Some promising drugs to treat tuberculosis, such as rifampin and bedaquiline, only kill nonreplicating at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating . With this goal, we review methods of high-throughput screening to target nonreplicating and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating revealed a rich diversity in pharmacophores.

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Strategies to evaluate the viability of nonreplicating mycobacteria for high-throughput screening. The arrow color indicates the quality of each readout strategy (considering robustness, ease of use, dynamic range, etc.) as excellent (green arrows), average to poor (black arrows), or infeasible (red line). Compound carryover may result from compound transfer from the nonreplicating assay to replicating assay bacteriologic growth medium or by compound adherence to the bacterial cell wall.

Source: microbiolspec February 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.TBTB2-0031-2016
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Selecting and designing nonreplicating (NR) models. Nonexhaustive list of models of class I and class II nonreplication. Variables to consider when designing models. Potential activity profiles of nonreplicating actives. The success of compounds targeting nonreplicating mycobacteria is dependent on the interactions among models, variables, and activity profiles. The term “DD Mtb” (ifferentially etectable ) is used interchangeably with “viable-but-nonculturable” (VBNC) .

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Compound transformation during screening assays. () Predicted, and experimentally validated, points of compound modification that may occur during phenotypic screening. In cell-free, nonreplicating conditions imposed by the multistress model, oxyphenbutazone (left) rapidly transforms in acidic and nitrosative conditions to the intermediate, 4-hydroxy-oxyphenbutazone (center), which further transforms to 4-hydroxy-oxyphenbutazone quinoneimine (right). The electrophilic quinoneimine (red) can react at carbon atoms (green) with intrabacterial nucleophiles such as -acetyl cysteine (NAC) and/or mycothiol (MSH).

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Proof-of-concept molecules. Molecules with nonreplicating activity that serve as proof of concept include those that selectively kill nonreplicating mycobacteria; have dual activity, kill mycobacteria in the majority of nonreplicating models, and are effective at treating tuberculosis in animal models; and have selective activity against slowly replicating or nonreplicating mycobacteria and are efficacious in tuberculosis models. n.t., not tested; *, pyrazinamide has activity against slowly replicating mycobacteria; #, experimental data indicate that pyrazinamide is inactive against intracellular mycobacteria ( 292 , 293 ). However, pyrazinamide’s dependency on an acidic environment for activity, and potent activity, suggests that it kills intracellular mycobacteria during animal and human tuberculosis.

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Canonical and noncanonical targets of dual-active molecules. Dual-active molecules, which have bacteriostatic or bactericidal activity against replicating and bactericidal activity against nonreplicating , are often presumed to engage the same target under both conditions. Dual-active molecules may exert activity against nonreplicating mycobacteria via novel targets or nonspecific mechanisms. The list of dual-active molecules is not exhaustive.

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Replicating and nonreplicating mycobacteria may share common targets. Examples of compounds that engage standard antibiotic target pathways under replicating conditions, and also kill nonreplicating mycobacteria, include inhibitors of the biosynthesis of lipids, DNA, RNA, protein, and peptidoglycan.

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Replicating and nonreplicating mycobacteria may share common targets. Examples of compounds that engage standard antibiotic target pathways under replicating conditions, and also kill nonreplicating mycobacteria, include inhibitors of the biosynthesis of lipids, DNA, RNA, protein, and peptidoglycan.

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Compounds targeting the proteostasis and proteolysis pathways.

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Representative compounds identified by whole-cell high-throughput screening (HTS) against mycobacteria rendered nonreplicating by carbon starvation ( 54 ); hypoxia ( 29 ); multiple stresses, including low pH, nitric oxide and reactive nitrogen intermediates, hypoxia, and a fatty acid carbon source ( 28 , 53 , 145 ); acidic pH ( 119 ); and culture as a biofilm ( 102 ).

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Nitro-containing compounds.

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Compounds that depolarize the mycobacterial membrane.

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Salicylanilides are protonophores. The commonly drawn structure of niclosamide (left). Compound S-13, which was used for experimental logP calculations ( 266 ), is shown for reference (right). As illustrated by niclosamide, salicylanilides capture protons by forming a stable pseudo-6-membered ring via hydrogen bonding. Once inside the bacterial cell and releasing their proton, they maintain a stable anionic form from electron delocalization. Adapted from Terada ( 266 ).

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Additional compounds that kill nonreplicating mycobacteria.

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Evaluating the relationship between hypoxia and metronidazole activity and

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Conditions encountered by that may contribute to suboptimal replication rates or complete growth stasis

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Postscreening assays for molecules active on replicating and/or nonreplicating

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Postscreening assays specific for nonreplicating active or candidate dual-active molecules (active on both replicating and nonreplicating bacilli)

Source: microbiolspec February 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.TBTB2-0031-2016

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