Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease currently treated using a drug regimen consisting of four drugs. Global TB control has been a persistent challenge for many decades due to the emergence of drug-resistant Mtb strains. The duration and complexity of TB treatment are the main issues leading to treatment failures. Other challenges faced by currently deployed TB regimens include drug-drug interactions, miss-matched pharmacokinetics parameters of drugs in a regimen, and lack of activity against slow replicating sub-population. These challenges underpin the continuous search for novel TB drugs and treatment regimens. This review summarizes new TB drugs/drug candidates under development with emphasis on their chemical classes, biological targets, mode of resistance generation, and pharmacokinetic properties. As effective TB treatment requires a combination of drugs, the issue of drug-drug interaction is, therefore, of great concern; herein, we have compiled drug-drug interaction reports, as well as efficacy reports for drug combinations studies involving antitubercular agents in clinical development.
Highlights
Tuberculosis (TB) is a contagious bacterial infection—one of the top ten causes of death, especially in young adults worldwide [1]
Mycobacterium tuberculosis (Mtb), a bacterium discovered by Dr Robert Koch in 1882, is the causative agent of TB, and it is a member of the Mycobacterium tuberculosis complex (MTBC)
The results indicated that the triple regimen exhibited at least a 1 log10 better killing of Mtb than the isoniazid/rifampicin combination, while the treatment with CPZEN-45 was as effective in reducing lung burden as isoniazid and better than rifampicin alone [165]
Summary
Tuberculosis (TB) is a contagious bacterial infection—one of the top ten causes of death, especially in young adults worldwide [1]. It was recognized that MFX used is associated with the risk of QT prolongation, and this risk increases when MFX is used in combination with drugs such as bedaquiline and delamanid [28]; careful safety monitoring is employed in these cases Another novel fluoroquinolone undergoing advanced clinical trial is gatifloxacin (GFX), a structural analog of MFX currently in phase III clinical trial. Grasela (2000) demonstrated that oral and intravenous administration of GFX produces equal dose-dependent Cmax, AUC, and clinical effects on participants regardless of gender or ethnicity This is comparable to findings from two independent studies consisting of healthy white and Japanese male subjects. DC-159a was found to exhibit the MIC90 of 0.5 μg/mL against the clinical MDR-Mtb isolates, which are resistant to other fluoroquinolones; for example, MFX and levofloxacin have higher MIC90 values of 4 and 16 μg/mL, respectively against the said strain [49]. Further evaluation to support substantiation of DC-159a as a novel agent for DS-TB, MDR-TB, XDR-TB, and TB/HIV coinfection cases, as well as further evaluation of intracellular pharmacokinetics and drug-drug interactions are required
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