Recent Progress in the Development of Novel Mycobacterium Cell Wall Inhibitor to Combat Drug-Resistant Tuberculosis

Abstract

Despite decades of research in drug development against TB, it is still the leading cause of death due to infectious diseases. The long treatment duration, patient noncompliance coupled with the ability of the tuberculosis bacilli to resist the current drugs increases multidrug-resistant tuberculosis that exacerbates the situation. Identification of novel drug targets is important for the advancement of drug development against Mycobacterium tuberculosis. The development of an effective treatment course that could help us eradicates TB. Hence, we require drugs that could eliminate the bacteria and shorten the treatment duration. This review briefly describes the available data on the peptidoglycan component structural characterization, identification of the metabolic pathway, and the key enzymes involved in the peptidoglycan synthesis, like N-Acetylglucosamine-1-phosphate uridyltransferase, mur enzyme, alanine racemase as well as their inhibition. Besides, this paper also provides studies on mycolic acid and arabinogalactan synthesis and the transport mechanisms that show considerable promise as new targets to develop a new product with their inhibiter.

Novel Approaches for the Treatment of Drug-Resistant Tuberculosis

“…It acts both in aerobic as well as anaerobic conditions and has activity against both drug-sensitive and DR-TB. [28] By inhibiting the synthesis of mycolic acid, [32] it leads to disruption of the cell wall of actively replicating Mtb bacilli, a death-inducing effect of Ptm. It also acts by its NO-releasing potential which kills anaerobic Mtb bacilli via respiratory poisoning.…”

Revolutionizing Tuberculosis Treatment: Uncovering New Drugs and Breakthrough Inhibitors to Combat Drug-Resistant Mycobacterium tuberculosis

“…Studies have shown that peptidomimetic substances and sulfonoxyanthranilic acid derivatives exhibit promising inhibitory activity against MurA. 26 compounds from different libraries that exhibited good pharmaceutical activity against MurA. These compounds included three from the ChemDiv library (D675-0217, D675-0102, and L291-0509) and three from the Asinex library (BDG 34016655, BDE 26717803, and BDE 25373574).…”

“…Several inhibitors, including sulfadoxine, pyrimethamine, and piperazine derivatives (Figure 1), have been identified using structurebased drug discovery methods. 26 MurE, also known as UDP-Nacetylmuramoylalanyl-D-glutamate-2,6-diaminopimelate ligase, adds m-DAP to UDP-MurNAc-L-Ala-D-Glu. Glucosamine uridine analogues have been found to inhibit MurE in the cell wall synthesis pathway (Figure 1).…”

“…Glucosamine uridine analogues have been found to inhibit MurE in the cell wall synthesis pathway (Figure 1). Recent studies have identified potential inhibitors of MTB-MurB, including chloropicolinate amides, 26 as shown in Figure 1 and Table 1.…”

Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity

“…As a prodrug, INH needs to be oxidized by the enzyme catalase-peroxidase (KatG) to inhibit its biological target enoyl-acyl carrier protein reductase (InhA), a critical enzyme employed in the biosynthesis of mycolic acids [ 6 , 7 ]. Therefore, the clinical efficacy of INH in the treatment of drug-resistant TB is restricted due to mutations in katG or inhA and its promoter [ 8 , 9 ]. Furthermore, in humans, INH is metabolized and in this way deactivated by N -acetyltransferase type 2 (NAT2).…”