Bactericidal mode of action of bedaquiline

Hards, Kiel; Robson, Jennifer R.; Berney, Michael; Shaw, Lisa E.; Bald, Dirk; Koul, Anil; Andries, Koen; Cook, Gregory M.

doi:10.1093/jac/dkv054

Cited by 182 publications

(261 citation statements)

References 32 publications

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“…2 C and D). TMC207 (1) is thought to target the ATP synthase in M. tuberculosis, but in recent work, it has also been proposed to act as an uncoupler, targeting again the ATP synthase (45). However, there is expected to be a significant protonophore contribution to its activity because clofazimine (17) (not thought to target the ATP synthase) and TMC207 (1) have almost identical logP, pK a , logD, and computed charge values (at pH 7.4) ( Table 1), even though the chemical structures are completely different.…”

Section: Resultsmentioning

confidence: 99%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

143

169

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There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.T here is a need for new antibiotics, due to the increase in drug resistance (1, 2). For example, some studies report that by 2050, absent major improvements in drug discovery and use, more individuals will die from drug-resistant bacterial infections than from cancer, resulting in a cumulative effect on global gross domestic product of as much as 100 trillion dollars (3, 4). To discover new drugs, new targets, leads, concepts, and implementations are needed (5, 6).Currently, one major cause of death from bacterial infections is tuberculosis (TB) (7), where very highly drug-resistant strains have been found (8). Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9-11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1). Bedaquiline (1) targets the Mycobacterium tuberculosis ATP synthase (9) whereas SQ109 (2) has been proposed to target MmpL3 (mycobacterial membrane protein large 3), a trehalose monomycolate transporter essential for cell wall biosynthesis (12). SQ109 (2) is a lipophilic base containing an adamantyl "headgroup" connected via an ethylene diamine "linker" to a geranyl (C 10 ) "side chain," and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent th...

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Section: Resultsmentioning

confidence: 99%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

143

169

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“…The F 1 F 0 ATPase is the target of bedaquiline, a novel antibiotic for the treatment of tuberculosis (50,51). The mechanism of action has been thought to be due to depletion of available energy currency (52); however, more recent analysis has revealed that it uncouples cellular respiration from ATP synthesis, resulting in a futile proton cycle that is linked to cell death (53). The degree of respiratory acceleration caused by knockout of the F 1 F 0 catalytic domain in E. coli in our study (Fig.…”

Section: Bacteriostatic Alterations To the Metabolome Correspond To Rmentioning

confidence: 99%

Antibiotic efficacy is linked to bacterial cellular respiration

Lobritz

Belenky

Porter

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

594

548

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Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes-the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy.

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“…333 A role for oxidative stress from the production of H 2 O 2 in the antibacterial mode of action of 334 PANI is supported by a) the supersensitivity of E. coli ΔkatG, which is unable to scavenge 335 endogenous H 2 O 2 and respond to the oxidative stress, and b) the decreased sensitivity of E. coli 336 342 based mechanism of action for PANI is derived from the greater sensitivity of the E. coli ΔiscS 343 mutant, which is unable to modify DNA for protection against oxidative stress . 344 The supersensitivity of the Spy mutant suggests that at least some of the damage is occurring in 345 Hards et al, 2015). There was evidence to imply damaged proteins may accumulate in the 358 periplasm following P3ABA exposure due to its proximity to the ETC and were inferred to 359 happen based on the insensitivity of the Spy mutant (which was hypothesised to have 360 upregulation of an additional extracytoplasmic stress response resulting in pre-adaption to 361 P3ABA action) (Raivio & Silhavy, 2001).…”

Section: Resultsmentioning

confidence: 99%

“…The decreased activity of P3ABA in anaerobic conditions 570 suggests that in rich media the antimicrobial activity of P3ABA involves a small amount of ROS 571 production. Uncoupling activity, such as what is postulated to occur during P3ABA action, 572 causes futile cycling, which is associated with increased oxygen consumption and production of 573 ROS (Adolfsen & Brynildsen, 2015;Hards et al, 2015). Therefore, the minor role of induction 574 of oxidative stress in P3ABA antimicrobial action may be due a downstream consequence of 575 uncoupling electron transport from ATP synthesis.…”

Section: B)mentioning

confidence: 99%

Peer Review #2 of "The antimicrobial action of polyaniline involves production of oxidative stress while functionalisation of polyaniline introduces additional mechanisms (v0.1)"

Bleackley¹

2018

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Polyaniline (PANI) and functionalised polyanilines (fPANI) are novel antimicrobial agents whose mechanism of action was investigated. Escherichia coli single gene deletion mutants revealed that the antimicrobial mechanism of PANI likely involves production of hydrogen peroxide while homopolymer poly(3-aminobenzoic acid), P3ABA, used as an example of a fPANI, disrupts metabolic and respiratory machinery, by targeting ATP synthase and causes acid stress. PANI was more active against E. coli in aerobic, compared to anaerobic, conditions, while this was apparent for P3ABA only in rich media.Greater activity in aerobic conditions suggests involvement of reactive oxygen species.P3ABA treatment causes an increase in intracellular free iron, which is linked to perturbation of metabolic enzymes and could promote reactive oxygen species production.Addition of exogenous catalase protected E. coli from PANI antimicrobial action; however, this was not apparent for P3ABA treated cells. The results presented suggest that PANI induces production of hydrogen peroxide, which can promote formation of hydroxyl radicals causing biomolecule damage and potentially cell death. P3ABA is thought to act as an uncoupler by targeting ATP synthase resulting in a futile cycle, which precipitates dysregulation of iron homeostasis, oxidative stress, acid stress, and potentially the fatal loss of proton motive force.PeerJ reviewing PDF |

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Bactericidal mode of action of bedaquiline

Cited by 182 publications

References 32 publications

Antiinfectives targeting enzymes and the proton motive force

Antiinfectives targeting enzymes and the proton motive force

Antibiotic efficacy is linked to bacterial cellular respiration

Peer Review #2 of "The antimicrobial action of polyaniline involves production of oxidative stress while functionalisation of polyaniline introduces additional mechanisms (v0.1)"

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