Abstract
ABSTRACTAs an obligate aerobe, Mycobacterium tuberculosis uses its electron transport chain (ETC) to produce energy via oxidative phosphorylation. This pathway has recently garnered a lot of attention and is a target for several new antimycobacterials. We tested the respiratory adaptation of M. tuberculosis to phenoxyalkylbenzimidazoles (PABs), compounds proposed to target QcrB, a component of the cytochrome bc1 complex. We show that M. tuberculosis is able to reroute its ETC to provide temporary resistance to PABs. However, combination treatment of PAB with agents targeting other components of the electron transport chain overcomes this respiratory flexibility. PAB in combination with clofazimine resulted in synergistic killing of M. tuberculosis under both replicating and nonreplicating conditions. PABs in combination with bedaquiline demonstrated antagonism at early time points, particularly under nonreplicating conditions. However, this antagonistic effect disappeared within 3 weeks, when PAB-BDQ combinations became highly bactericidal; in some cases, they were better than either drug alone. This study highlights the potential for combination treatment targeting the ETC and supports the development of PABs as part of a novel drug regimen against M. tuberculosis.
Highlights
As an obligate aerobe, Mycobacterium tuberculosis uses its electron transport chain (ETC) to produce energy via oxidative phosphorylation
M. tuberculosis has a respiratory flexibility that responds to the inhibition of QcrB by upregulating the alternative cytochrome bd oxidase [15, 16]
This response has been seen with several different compound series which apparently target QcrB directly [16]. To determine whether this holds true for PAB compounds, we looked at the ability of the PAB series to inhibit bacterial growth against different variants of M. tuberculosis H37Rv (Fig. 1)
Summary
Mycobacterium tuberculosis uses its electron transport chain (ETC) to produce energy via oxidative phosphorylation. This pathway has recently garnered a lot of attention and is a target for several new antimycobacterials. We tested the respiratory adaptation of M. tuberculosis to phenoxyalkylbenzimidazoles (PABs), compounds proposed to target QcrB, a component of the cytochrome bc complex. There is an alarming increase in the rate of multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis, which lengthens the normal drug regimen from 6 months to 2 years but still causes a mortality rate in treated individuals of ϳ50% Given these facts, there is a dire need for the discovery of novel preventatives and therapeutics to combat M. tuberculosis infections. We recently identified the probable target of PABs to be QcrB [32], indicating that this series of compounds likely works by inhibiting the cytochrome bc reductase
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