Pravin S. Shirude

Aminopyrazinamides: Novel and Specific GyrB Inhibitors that Kill Replicating and Nonreplicating Mycobacterium tuberculosis

Aminopyrazinamides originated from a high throughput screen targeting the Mycobacterium smegmatis (Msm) GyrB ATPase. This series displays chemical tractability, robust structure-activity relationship, and potent antitubercular activity. The crystal structure of Msm GyrB in complex with one of the aminopyrazinamides revealed promising attributes of specificity against other broad spectrum pathogens and selectivity against eukaryotic kinases due to novel interactions at hydrophobic pocket, unlike other known GyrB inhibitors. The aminopyrazinamides display excellent mycobacterial kill under in vitro, intracellular, and hypoxic conditions.

1,4-Azaindole, a Potential Drug Candidate for Treatment of Tuberculosis

ABSTRACT New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1). Further, this series was optimized to improve its physicochemical properties and pharmacokinetics in mice. Here, we describe the short-listing of a potential clinical candidate, compound 2, that has potent cellular activity, drug-like properties, efficacy in mouse and rat chronic TB infection models, and minimal in vitro safety risks. We also demonstrate that the compounds, including compound 2, have no antagonistic activity with other anti-TB drugs. Moreover, compound 2 shows synergy with PA824 and TMC207 in vitro, and the synergy effect is translated in vivo with TMC207. The series is predicted to have a low clearance in humans, and the predicted human dose for compound 2 is ≤1 g/day. Altogether, our data suggest that a 1,4-azaindole (compound 2) is a promising candidate for the development of a novel anti-TB drug.

Nonfluoroquinolone-Based Inhibitors of Mycobacterial Type II Topoisomerase as Potential Therapeutic Agents for TB

Abstract Mycobacterium tuberculosis is a difficult pathogen to combat and the first-line drugs currently in use are 40–60 years old. The need for new TB drugs is urgent, in order to stem the tide of the disease globally and develop new, more effective treatments against drug-sensitive and -resistant strains. DNA gyrase, a class of enzymes known as topoisomerases, has attracted considerable attention as a potential antimycobacterial target. These enzymes are involved in the crucial processes of DNA replication, transcription, translation, and recombination in prokaryotic and eukaryotic cell regulation of DNA topology and its degree of supercoiling. DNA gyrase has no direct counterpart in eukaryotes. The indispensable nature of gyrase in the bacterial cells makes DNA gyrase an ideal drug target. Novobiocin and coumermycin inhibit DNA gyrase by binding to the ATP sites in GyrB, while the quinolone class inhibits these enzymes by binding to a site in GyrA near the intersection of the subunits and the associated DNA strand. This review broadly organizes small-molecule inhibitors of bacterial type II topoisomerase into GyrB inhibitors and nonfluoroquinolone-based GyrA inhibitors.

Chapter Fourteen - Advancement of Cell Wall Inhibitors in Mycobacterium tuberculosis

Abstract Despite decades of scientific progress, tuberculosis (TB) still remains a major global health problem. The first-line and second-line anti-TB drugs include compounds that inhibit some part of Mycobacterium tuberculosis (Mtb) cell wall synthesis or metabolism. The recent understanding of “cell wall core” activity in the different stages of infection in vivo has highlighted the importance of cell wall inhibitors targeting both replicating and nonreplicating Mtb. Therefore, most of the newly discovered compounds emphasize the cell wall as the target of choice for Mtb. Drug-to-target screening approaches have identified novel targets impacting major cell wall components (e.g., DprE1, MmpL3, and others) in addition to better known targets (InhA, peptidoglycan synthesis). Novel cell wall inhibitors provide a potential new therapy to address drug-resistant TB in patients who are resistant to existing first- and second-line drugs. This review broadly describes recent advances in targeting the cell wall of Mtb, with specific focus on InhA, DprE1, MmpL3, and peptidoglycan biosynthesis.Abstract Despite decades of scientific progress, tuberculosis (TB) still remains a major global health problem. The first-line and second-line anti-TB drugs include compounds that inhibit some part of Mycobacterium tuberculosis (Mtb) cell wall synthesis or metabolism. The recent understanding of “cell wall core” activity in the different stages of infection in vivo has highlighted the importance of cell wall inhibitors targeting both replicating and nonreplicating Mtb. Therefore, most of the newly discovered compounds emphasize the cell wall as the target of choice for Mtb. Drug-to-target screening approaches have identified novel targets impacting major cell wall components (e.g., DprE1, MmpL3, and others) in addition to better known targets (InhA, peptidoglycan synthesis). Novel cell wall inhibitors provide a potential new therapy to address drug-resistant TB in patients who are resistant to existing first- and second-line drugs. This review broadly describes recent advances in targeting the cell wall of Mtb, with specific focus on InhA, DprE1, MmpL3, and peptidoglycan biosynthesis.