Tuberculosis Clinical Trial Update and the Current Anti-Tuberculosis Drug Portfolio

Abstract

Tuberculosis (TB), an ongoing public health threat, is worsened by the emergence of drug resistance. With an estimated 630000 cases per year of multidrug resistant (MDR)-TB, and 9% of those being extensively drug resistant (XDR)-TB, there is an urgent need for new and more effective anti-TB drugs. New TB treatment regimens should be able to shorten the duration of therapy that currently takes at least six months. The non-compliance with this long treatment duration is one of the reasons for the development of drug resistance. In spite of the difficulties and alleged lack of interest from the pharmaceutical industry for the discovery and development of new antibiotics, several new or repurposed drugs are being evaluated in clinical trials. This review article summarizes the information available and presents an update on the drugs currently in clinical trials for TB and briefly introduces some new compounds in pre-clinical development.

Drug Resistance Mechanisms in Mycobacterium tuberculosis

“…Both ciprofloxacin and ofloxacin are synthetic derivatives of the parent compound nalidixic acid, discovered as a by-product of the antimalarial chloroquine [ 72 ]. Newer-generation quinolones such as moxifloxacin and gatifloxacin are being evaluated in clinical trials and proposed as first-line antibiotics with the purpose of shortening the length of treatment in TB [ 73 , 74 ].…”

“…Bedaquiline was discovered after a high-throughput evaluation of thousands of compounds using Mycobacterium smegmatis in a whole-cell assay [ 117 ]. The drug showed in vitro and in vivo activity against M. tuberculosis and then entered into clinical evaluation for drug susceptible and MDR-TB [ 74 , 118 , 119 ]. Based on the results of two phase II clinical trials, bedaquiline has recently received conditional approval for the treatment of MDR-TB under the trade name Sirturo.…”

Quinoxaline, its derivatives and applications: A State of the Art review

“…However, due to the arising of multidrug resistant (MDR) TB it is required the development of new therapeutic agents, with a unique mechanism of action, able to treat MDR forms of the disease [26]. Several studies have been described, concerning synthesis and biological activity of a large amount of quinoxalines and 1,4-di-Noxide quinoxaline derivatives, where compounds such as 7-chloro-3-(p-substituted)-phenylaminoquinoxaline-2-carbonitrile-1,4-di-N-oxide, 6,7-dichloro-2-ethoxycarbonyl-3-methylquinoxaline-1,4-di-N-oxide and 3-acetamide-6,7-dichloroquinoxaline-2-carbonitrile-1,4-di-N-oxide derivatives have been shown to possess M. tuberculosis growth inhibition values from 99 to 100% [21,27].…”

Induction of CYP2E1 in testes of isoniazid-treated rats as possible cause of testicular disorders

“…In general, all patients from countries with a known high incidence of resistant Mycobacterium tuberculosis strains, all patients who had been treated previously, and all patients with life-threatening tuberculosis, receive as initial anti-tuberculosis therapy the same combination of isoniazid (INH), rifampin (RMP) and pyrazinamide (PZA), together with at least one additional medicine (ethambutol (EMB) and/or streptomycin) (Palomino and Martin, 2013).…”