Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery

Iqbal, Iram Khan; Bajeli, Sapna; Akela, Ajit Kumar; Kumar, Ashwani

doi:10.3390/pathogens7010024

Cited by 54 publications

(61 citation statements)

References 202 publications

(275 reference statements)

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“…BDQ is the first-in-class ATP synthase inhibitor which displays high selectivity toward mycobacterial ATP synthase and therefore renders the bacterium low on energy. Furthermore, it has been reported that, upon BDQ treatment, major metabolic alterations occur in the cell and several biosynthetic processes are downregulated (19,25). Hence, we were tempted to explore if the atpD-knockout strain mimics BDQ-treated wild-type M. smegmatis.…”

Section: Discussionmentioning

confidence: 99%

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Insights into the Physiology and Metabolism of a Mycobacterial Cell in an Energy-Compromised State

Patil

Jain

2019

J Bacteriol

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Mycobacterium tuberculosis, a bacterium that causes tuberculosis, poses a serious threat, especially due to the emergence of drug-resistant strains. M. tuberculosis and other mycobacterial species, such as M. smegmatis, are known to generate an inadequate amount of energy by substrate-level phosphorylation and mandatorily require oxidative phosphorylation (OXPHOS) for their growth and metabolism. Hence, antibacterial drugs, such as bedaquiline, targeting the multisubunit ATP synthase complex, which is required for OXPHOS, have been developed with the aim of eliminating pathogenic mycobacteria. Here, we explored the influence of suboptimal OXPHOS on the physiology and metabolism of M. smegmatis. M. smegmatis harbors two identical copies of atpD, which codes for the β subunit of ATP synthase. We show that upon deletion of one copy of atpD (M. smegmatis ΔatpD), M. smegmatis synthesizes smaller amounts of ATP and enters into an energy-compromised state. The mutant displays remarkable phenotypic and physiological differences from the wild type, such as respiratory slowdown, reduced biofilm formation, lesser amounts of cell envelope polar lipids, and increased antibiotic sensitivity compared to the wild type. Additionally, M. smegmatis ΔatpD overexpresses genes belonging to the dormancy operon, the β-oxidation pathway, and the glyoxylate shunt, suggesting that the mutant adapts to a low energy state by switching to alternative pathways to produce energy. Interestingly, M. smegmatis ΔatpD shows significant phenotypic, metabolic, and physiological similarities with bedaquiline-treated wild-type M. smegmatis. We believe that the identification and characterization of key metabolic pathways functioning during an energy-compromised state will enhance our understanding of bacterial adaptation and survival and will open newer avenues in the form of drug targets that may be used in the treatment of mycobacterial infections. IMPORTANCE M. smegmatis generates an inadequate amount of energy by substrate-level phosphorylation and mandatorily requires oxidative phosphorylation (OXPHOS) for its growth and metabolism. Here, we explored the influence of suboptimal OXPHOS on M. smegmatis physiology and metabolism. M. smegmatis harbors two identical copies of the atpD gene, which codes for the ATP synthase β subunit. Here, we carried out the deletion of only one copy of atpD in M. smegmatis to understand the bacterial survival response in an energy-deprived state. M. smegmatis ΔatpD shows remarkable phenotypic, metabolic, and physiological differences from the wild type. Our study thus establishes M. smegmatis ΔatpD as an energy-compromised mycobacterial strain, highlights the importance of ATP synthase in mycobacterial physiology, and further paves the way for the identification of novel antimycobacterial drug targets.

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Section: Discussionmentioning

confidence: 99%

“…ATP synthase is essential for mycobacterial survival in both the replicating and dormant states (18,19,25). Thus, inhibition of this essential pathway via any means is, in all likelihood, bound to affect the key metabolic pathways in the cell.…”

mentioning

confidence: 99%

Insights into the Physiology and Metabolism of a Mycobacterial Cell in an Energy-Compromised State

Patil

Jain

2019

J Bacteriol

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“…Interestingly, targeting cytochrome P450 enzymes in M. tuberculosis has also been proposed as the source of a potential new class of drugs for treating MDR-TB [ 78 ]. Similarly, targeting oxidative phosphorylation (NADH dehydrogenase, menaquinone biosynthesis, terminal oxidase, and ATP synthase) with specific inhibitors (phenothiazine derivatives, DG70, imidazopyridine amides, and diarylquinolines), in combination with antitubercle drugs, is an exciting novel avenue for short-term and effective treatment [ 79 ]. Notably, inhibiting bacterial oxidative phosphorylation may also result in limiting the formation of “persisters” in the host.…”

Section: Potential New Tb Therapies Targeting the Oxidant : Antioxmentioning

confidence: 99%

Role of Oxidative Stress in the Pathology and Management of Human Tuberculosis

Shastri

Shukla

Chong

et al. 2018

Oxidative Medicine and Cellular Longevity

117

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Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, is the leading cause of mortality worldwide due to a single infectious agent. The pathogen spreads primarily via aerosols and especially infects the alveolar macrophages in the lungs. The lung has evolved various biological mechanisms, including oxidative stress (OS) responses, to counteract TB infection. M. tuberculosis infection triggers the generation of reactive oxygen species by host phagocytic cells (primarily macrophages). The development of resistance to commonly prescribed antibiotics poses a challenge to treat TB; this commonly manifests as multidrug resistant tuberculosis (MDR-TB). OS and antioxidant defense mechanisms play key roles during TB infection and treatment. For instance, several established first-/second-line antitubercle antibiotics are administered in an inactive form and subsequently transformed into their active form by components of the OS responses of both host (nitric oxide, S-oxidation) and pathogen (catalase/peroxidase enzyme, EthA). Additionally, M. tuberculosis has developed mechanisms to survive high OS burden in the host, including the increased bacterial NADH/NAD+ ratio and enhanced intracellular survival (Eis) protein, peroxiredoxin, superoxide dismutases, and catalases. Here, we review the interplay between lung OS and its effects on both activation of antitubercle antibiotics and the strategies employed by M. tuberculosis that are essential for survival of both drug-susceptible and drug-resistant bacterial subtypes. We then outline potential new therapies that are based on combining standard antitubercular antibiotics with adjuvant agents that could limit the ability of M. tuberculosis to counter the host's OS response.

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“…Additionally, the MK/MKH can also be reduced by alternative electron donors, e.g., via the succinate dehydrogenase (SDH). Electrons can be transferred directly from the MK/MKH to the cytochrome bc 1- aa 3 complex or alternatively, the oxygen can be reduced by a cytochrome bd -type terminal oxidase, which directly accepts electrons from the MK/MKH (Black et al, 2014 ; Bald et al, 2017 ; Iqbal et al, 2018 ). The proton gradient generated through oxidative phosphorylation leads to ATP synthesis via the ATP synthase which is responsible for the conversion of the electrochemical potential energy generated by the PMF into chemical energy in the form of ATP (Feniouk et al, 2007 ).…”

Section: Tuberculosis Biology Challenges: Focus On Energymentioning

confidence: 99%

Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

et al. 2018

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The emergence of multi- and extensively drug resistant tuberculosis worldwide poses a great threat to human health and highlight the need to discover and develop new, effective and inexpensive antituberculosis agents. High-throughput screening assays against well-validated drug targets and structure based drug design have been employed to discover new lead compounds. However, the great majority fail to demonstrate any antimycobacterial activity when tested against Mycobacterium tuberculosis in whole-cell screening assays. This is mainly due to some of the intrinsic properties of the bacilli, such as the extremely low permeability of its cell wall, slow growth, drug resistance, drug tolerance, and persistence. In this sense, understanding the pathways involved in M. tuberculosis drug tolerance, persistence, and pathogenesis, may reveal new approaches for drug development. Moreover, the need for compounds presenting a novel mode of action is of utmost importance due to the emergence of resistance not only to the currently used antituberculosis agents, but also to those in the pipeline. Cheminformatics studies have shown that drugs endowed with antituberculosis activity have the peculiarity of being more lipophilic than many other antibacterials, likely because this leads to improved cell penetration through the extremely waxy mycobacterial cell wall. Moreover, the interaction of the lipophilic moiety with the membrane alters its stability and functional integrity due to the disruption of the proton motive force, resulting in cell death. When a ligand-based medicinal chemistry campaign is ongoing, it is always difficult to predict whether a chemical modification or a functional group would be suitable for improving the activity. Nevertheless, in the “instruction manual” of medicinal chemists, certain functional groups or certain physicochemical characteristics (i.e., high lipophilicity) are considered red flags to look out for in order to safeguard drug-likeness and avoid attritions in the drug discovery process. In this review, we describe how antituberculosis compounds challenge established rules such as the Lipinski's “rule of five” and how medicinal chemistry for antituberculosis compounds must be thought beyond such dogmatic schemes.

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Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery

Cited by 54 publications

References 202 publications

Insights into the Physiology and Metabolism of a Mycobacterial Cell in an Energy-Compromised State

Insights into the Physiology and Metabolism of a Mycobacterial Cell in an Energy-Compromised State

Role of Oxidative Stress in the Pathology and Management of Human Tuberculosis

Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

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