Mycobacterium Tuberculosis - Paper Example

Mycobacterium tuberculosis is an obligate anaerobe and synthesizes its energy through oxidative phosphorylation pathway and the electron transport chain (ETC). M. tuberculosis causes tuberculosis, which is a leading cause of infectious-disease-associated deaths globally (Berube & Parish, 2018; Cook et al., 2013). In 2015, there were approximately 11 million new infections, and the disease resulted in 1.8 million deaths (Berube & Parish, 2018). This review provides an insight, which is founded on evidence-based publications, on the feasibility of the ETC and respiratory pathway of the M. tuberculosis as a drug target.

The need for innovative approaches to identify new drug targets and develop new agents targeting different targets is influenced by the emergence of drug-resistant M. tuberculosis strains. The extremely drug resistant (EDR) and multi-drug resistant (MDR) mycobacterial infections pose major public health threats across the world. Some of the impacts associated with mycobacterial infections include socioeconomic burdens and high mortality rate (Bald et al., 2017; Berube & Parish, 2018). About $12 billion is spent annually globally for managing the disease and catering for associated costs (Berube & Parish, 2018). Agents target mycobacterial oxidative phosphorylation pathway will transform TB treatment and influence a widespread shift in the manner in which bacterial infections are managed and treated.

Energy metabolism has been widely described in the previous literature as a potential target for treating the diseases caused by infectious agents (Bald et al., 2017). Bacteria synthesize ATP by oxidative phosphorylation via the oxidative phosphorylation pathway or by deriving it from fermentable carbon sources through substrate-level phosphorylation. M. tuberculosis has undergone significant level of mutagenesis and genetic deletions that have significantly interfered with its capacity to gain enough energy through by substrate-level phosphorylation. Thus, it heavily relies on oxidative phosphorylation for growth and survival (Bald et al., 2017).

Mycobacteria inhabit highly dynamic environments. It includes extracellular ad intracellular environments. M. tuberculosis has developed mechanisms that enable it to sustain growth and survival through active redirection of its metabolic activity. M. tuberculosis has evolved the capacity to regenerate the reducing equivalents, respire, and to synthesize adenosine triphosphate (ATP) through oxidative phosphorylation. Mycobacteria are armed with various dehydrogenases that catalyze different steps of the ETC. It also has two terminal oxidases, namely cytochrome bd-type menaquinol oxidase and the aa3-type cytochrome c oxidase, whose functions are as described below (Cook et al., 2013).

Oxidative phosphorylation pathway in M. tuberculosis has attracted more attention across different researchers as a potential target for novel chemotherapeutic agents (Anand et al., 2015; Bald et al., 2017; Cook et al., 2013; Sukheja et al., 2017). In oxidative phosphorylation pathway, electrons that are generated from nicotinamide adenine dinucleotide (NADH) are transferred into the ETC by NADH dehydrogenase resulting the degeneration of the menaquinone pool (MK/MKH2 where MK is menaquinone and MKH2 is the reduced menaquinone). Type I NADH dehydrogenase is unessential for growth in M. tuberculosis. Mycobacteria utilize type II NADH dehydrogenase (NDH-2) instead. M. tuberculosis has two copies of the NDH-2. The substitute electron donors such as succinate dehydrogenase (SDH) can reduce the menaquinone pool. M. tuberculosis has one form of the fumarate reductase enzyme and two variants of the succinate dehydrogenase enzymes (i.e., Sdh-1 and Sdh-2). Fumarate reductase catalyzes the reverse-reaction (Bald et al., 2017).

Electrons derived from the menaquinone pool are then transported to the cytochrome c reductase (bc1) complex. In M. tuberculosis, the cytochrome aa3-type terminal oxidase forms a super-complex with the cytochrome bc1 to form bc1:aa3 complex (Bald et al., 2017; Kalia et al., 2017). The bc1:aa3 complex consists of menaquinone. Menaquinone is formed by the cytochrome bc1 and cytochrome aa3-typeoxidase (Kalia et al., 2017). The super-complex transports electrons into oxygen resulting in the reduction of oxygen. On the other hand, oxygen reduction can occur through the effect of the cytochrome bd-type terminal oxidase that directly accepts electron donation from the menaquinone pool (Bald et al., 2017).

The process of electron transfer through a respiratory chain co-occurs with proton pumping through the membrane resulting in what is termed as a proton motive force (PMF) that develops across a biomembrane. Energy derived from PMF is utilized by mycobacteria for the ATP synthesis through a process that is catalyzed by ATP synthase. Maintenance of PMF, the inflow of electrons, and ATP synthesis by oxidative phosphorylation is indispensable for M. tuberculosis survival and growth (Bald et al., 2017).

Fumarate reductase is essential for maintaining PMF in M. tuberculosis under anaerobic conditions whereas Sdh-1 is essential for regulating mycobacterial oxidative phosphorylation process aiding its adaptation to the low-oxygen conditions (Bald et al., 2017). The adaptation to hypoxic conditions is considered one of the main strategies employed by M. tuberculosis to maintain a sustained dormant persistence in humans (Anand et al., 2015). Similarly, M. tuberculosis and M. smegmatis can synthesize polyketide quinones (PkQs) as alternative metabolites for maintaining cellular bioenergetics through the respiratory ETC. PkQs are synthesized by type III polyketide synthases through utilization of the fatty acyl-CoA precursors. PkQs act as mobile electron carriers in the oxidation ETC. In the absence of PkQs metabolites, mycobacteria tend to leave the biofilms and seek oxygen-rich niche for growth and survival (Anand et al., 2015).

Latent M. tuberculosis cells have a reduced metabolic activity making them difficult to be cleared by rifampicin and isoniazid. The persistent mycobacterial cells after chemotherapy results in the emergence of drug-resistant strains (Vilcheze et al., 2017). Latent infections are associated with the behavior of mycobacteria to form biofilm and cease its replication making it difficult to treat with existing conventional agents (Sukheja et al., 2017). However, agents that will block synthesis of PkQs metabolites may force M. tuberculosis to end its latency state and exit the biofilm, making it more susceptible to existing anti-TB drugs (Anand et al., 2015; Sukheja et al., 2017).

Innovative drugs inhibiting energy metabolism are equally effective against both drug-susceptible and drug-resistant strains of M. tuberculosis. Novel antibacterial classes, which target the oxidative phosphorylation pathway in M. tuberculosis, have shown significant activity in treating latent mycobacterial infections (Bald et al., 2017). Latent and active TB infections require an extended pharmocotherapeutic period to realize durable cures (Sukheja et al., 2017). Agents targeting energy metabolic pathways have a potential of shortening pharmacotherapy period for TB (Berube & Parish, 2018).

Current standard chemotherapeutic for the drug-susceptible form of the disease is period is six months with four first-line agents. Besides, MDR-TB, which is characterized by resistance a minimum of two of the four first-line drugs, is currently treated for 18 24 months with 4 6 drugs (Bald et al., 2017). MDR-TB and XDR-TB may be treated by a combined drug therapy can still result in death in about 50% of the treated cases (Berube & Parish, 2018). XDR-TB is characterized by expression of additional resistance to fluoroquinolones and resistant to any (or more) second-line agent. The extended period of chemotherapeutic intervention increases the risk of emergence of the drug-resistant strains (Bald et al., 2017). In the foreseeable future, agents that will be inhibiting the M. tuberculosis energy metabolic pathways may reduce the risk of occurrence of drug-resistant strains by shortening the treatment period (Bald et al., 2017).

New agents have already been developed targeting oxidative phosphorylation pathway in mycobacteria. These agents include the U.S. Food and Drug Administration (FDA) approved nitroimidazo-oxazole delamanid and dairylquinoline bedaquiline (BDQ). The safety and efficacy of the two drugs are under investigation in phase 3 of the clinical trials. BDQ is an effective inhibitor of the mycobacterial ATP-synthase. BDQ is validated the oxidative phosphorylation pathway as a drug target for treating TB. It has also been demonstrated that small-molecule agents (currently in the pre-clinical stage) targeting the mycobacterial oxidative phosphorylation pathway are active against both drug-resistant and drug-sensitive TB. The small-molecule inhibitors act by breaking down PMF, prevention of respiratory electron transfer, and blocking ATP synthesis (Bald et al., 2017).

Clofazimine and phenothiazine classes of drugs, in which both have been approved by U.S. FDA, target NDH-2 in the oxidative phosphorylation pathway. They have important uses for treatment of MDR-TB. However, clofazimine was initially approved for the management of leprosy but have been repurposed for use against MDR-TB. Similarly, Phenothiazines were approved as antipsychotic agents but have also been repurposed for TB (Bald et al., 2017). Imidazopyridines (Q203), which is currently at phase 1 of clinical trials, target cytochrome bc1 complex but it is characterized by bacteriostatic activity but has limited activity in the clearance of latent infections (Bald et al., 2017; Kalia et al., 2017). Imidazopyridines were discovered through phenotypic screening of M. tuberculosis in macrophages. The phenotypic high-throughput screening-discovered diarylquinolines (approved at phase 3) against M. smegmatis has shown potent inhibitory activity on M. tuberculosis ATP synthase and in other related strains. Squaramides are another relatively new class of M. tuberculosis ATP synthase (Bald et al., 2017).

Q203 is described as a small molecule that targets the M. tuberculosis cytochrome bc1:aa3 complex. Q203 demonstrate a high affinity to the mycobacterial cytochrome bc1:aa3 complex. The alternate cytochrome bd oxidase is adequate for maintain the ETC, menaquinol oxidation, and PMF in the presence of Q203. Electron flow through the cytochrome bd oxidase is adequate for the mycobacterial synthesis of ATP and essential respiratory level, hence sustaining mycobacterial growth and survival and evading Q203-induced death. However, when the cytochrome bd oxidase-encoding gene (cydAB) gene is deleted Q203 exhibits bactericidal activity towards mycobacteria by completely blocking ETC, as well as activity against persistent drug-resistant strains. These findings indicate that novel agents targeting cytochrome enzymes and their complexes should target both cytochrome bc1:aa3 complex and the cytochrome bd oxidase (Kalia et al., 2017).

Another study overcomes the above challenge by employing different agents that target various components of the ETC. It was established that phenoxyalkylbenzidazoles alone, targeting QcrB, which forms part of the cytochrome bc1 complex, had no bactericidal activity against M. tuberculosis. M. tuberculosis could compensate inadequacies in the cytochrome bc1 through utilization of alternative pathways. M. tuberculosis can reroute its ETC pathway to foster its survival and growth. However, the combined therapy comprising of phenoxyalkylbenzidazoles and clofazimine led to as significant synergistic bactericidal activity under both non-replicating and replica...