Unraveling Dilemmas and Lacunae in the Escalating Drug Resistance of Mycobacterium tuberculosis to Bedaquiline, Delamanid, and Pretomanid

Abstract

Delamanid, bedaquiline, and pretomanid have been recently added in the anti-tuberculosis (anti-TB) treatment regimens and have emerged as potential solutions for combating drug-resistant TB. These drugs have proven to be effective in treating drug-resistant TB when used in combination. However, concerns have been raised about the eventual loss of these drugs due to evolving resistance mechanisms and certain adverse effects such as prolonged QT period, gastrointestinal problems, hepatotoxicity, and renal disorders. This Perspective emphasizes the properties of these first-in-class drugs, including their mechanism of action, pharmacokinetics/pharmacodynamics profiles, clinical studies, adverse events, and underlying resistance mechanisms. A brief coverage of efforts toward the generation of best-in-class leads in each class is also provided. The ongoing clinical trials of new combinations of these drugs are discussed, thus providing a better insight into the use of these drugs while designing an effective treatment regimen for resistant TB cases. ■ SIGNIFICANCE• The approval of delamanid, bedaquiline, and pretomanid constitutes a significant breakthrough in addressing drug-resistant tuberculosis. • Despite initial success, resistance mechanisms have emerged against these drugs. The current Perspective addresses this issue by shedding light on the specific mutations and mechanisms responsible for the resistance. • This Perspective assesses the current status of these firstin-class drugs and explores "best-in-class" drugs as potential leads to enhance efficacy and counter resistance.

Host Cell Death and Modulation of Immune Response against Mycobacterium tuberculosis Infection

“…Unfortunately, standard antibiotic therapy involves expensive long-term treatment and side effects and has led to the development of multi-drug-resistant TB [ 171 ]. Alternative antibiotics and nitroimidazoles, such as delamanid and pretomanid, have been investigated; however, concerns exist over their resistance and side effects [ 172 ]. Experimentation with alternative therapies, such as the utilization of bacteriophages to deliver lytic enzymes, has been proposed as adjunctive therapy for current treatment regimens, but such approaches remain experimental [ 173 ].…”