Analysis of Approaches to Anti-tuberculosis Compounds

Abstract

Mycobacterium tuberculosis (Mtb) remains a deadly pathogen two decades after the announcement of tuberculosis (TB) as a global health emergency by the World Health Organization. Medicinal chemistry efforts to synthesize potential drugs to shorten TB treatments have not always been successful. Here, we analyze physiochemical properties of 39 TB drugs and 1271 synthetic compounds reported in 40 publications from 2006 to early 2020. We also propose a new TB space of physiochemical properties that may provide more appropriate guidelines for design of anti-TB drugs.

Structure-based in silico approaches for drug discovery against Mycobacterium tuberculosis

“…When selection of follow-up hits is being undertaken on the basis of physiochemical properties, it should be noted that the current TB-drug space has significantly different physiochemical properties in comparison to those specified by the Lipinski’s rule of five [32] , [147] . The difference in compound properties is in part due to the hydrophobic M. tuberculosis cell envelope, which prevents penetration of many drug compounds.…”

Deciphering the mechanism of action of antitubercular compounds with metabolomics

“…The standard care for TB patients involves two months of treatments with a four drug cocktail (isoniazid, rifampicin, pyrazinamide, and ethambutol) followed by four additional months of treatment with rifampicin and isoniazid [5] , [12] , [13] . This drug-treatment regimen is currently used for the majority of TB cases and has an 80–90% success rate for patients infected with drug-sensitive M. tb .…”

“…This drug-treatment regimen is currently used for the majority of TB cases and has an 80–90% success rate for patients infected with drug-sensitive M. tb . Please see Table 1 for the current list of antituberculosis drugs used in the treatment of TB [5] . Conversely, an MDR-TB regimen requires at least 18 months of treatments with five or more TB drugs that include second-line and injectable drugs that are known to be more toxic, inefficient, and poorly tolerated.…”

“…Conversely, an MDR-TB regimen requires at least 18 months of treatments with five or more TB drugs that include second-line and injectable drugs that are known to be more toxic, inefficient, and poorly tolerated. The current treatment of MDR-TB only has a cure rate of 60–70% [5] , [14] . Unfortunately, treatment outcomes for pre-extensively drug resistant TB (Pre-XDR TB) and XDR-TB patients are still poor [15] , [16] .…”

“…In particular, the emergence of rifampicin resistant (RR-TB), multi-drug resistant (MDR-TB), or extensively drug-resistant (XDR-TB) forms of M. tb. has only exasperated the worldwide health crisis [5] . Globally, over two hundred thousand people tested positive for MDR-TB or RR-TB in 2019; this represents a 10% increase from 2018 [4] .…”