Cyclic AMP-Mediated Inhibition of Cholesterol Catabolism in Mycobacterium tuberculosis by the Novel Drug Candidate GSK2556286

Abstract

Despite the deployment of combination tuberculosis (TB) chemotherapy, efforts to identify shorter, nonrelapsing treatments have resulted in limited success. Recent evidence indicates that GSK2556286 (GSK286), which acts via Rv1625c, a membrane-bound adenylyl cyclase in Mycobacterium tuberculosis , shortens treatment in rodents relative to standard of care drugs.

Cholesterol-Mediated Coenzyme A Depletion in Catabolic Mutants of Mycobacteria Leads to Toxicity

“…By contrast, COCHEA-CoA is not detected in WT cells growing on cholesterol. 15,30 Similarly, the ΔipdF and ΔechA20 mutants both contained high amounts of 3aα-H-4α(carboxyl-CoA)-5-hydroxy-7aβ-methylhexahydro-1-indanone-CoA (5OH-HIC-CoA; Figure 1) (Figure 3B), consistent with previous findings. 8 Interestingly, while all strains showed the accumulation of cholesterol-derived acyl-CoAs, the ΔipdAB mutant was more significantly depleted in free CoASH and showed a greater cholesterol-dependent toxicity (Figure 3C).…”

Updates in pulmonary drug‐resistant tuberculosis pharmacotherapy: A focus on BPaL and BPaLM

“…There are numerous anti-TB drugs in clinical and pre-clinical studies to evaluate novel mechanisms of action to treat TB. A small list of agents that exist in current pipeline development that may be useful for treating drug-resistant TB are listed in Diarylquinolines TBAJ-876 I and II [111,112] TBAJ-587 I [113] Diarylpyridine Sudapyridine (WX-081) II [90,91] Amido piperidine BVL-GSK098 II [114] Aminobenzimidazole SPR720 (Fobrepodacin) II (early D/C) [115] Oxaborole GSK 3036656 II [116,117] Cytochrome bc1 complex inhibitor Telacebec II [118] DprE1 inhibitor BTZ-043 IIa [119] TBA-7371 (AZ 7371) II [92,120] Macozinone (PBTZ-169) I (IIa terminated) [92,121] OPC-167832 II [92,122] Ethylenediamine SQ109 II [123,124] Rv1625c agonist GSK-286 (GSK2556286) I [125,126] Riminophenazines TBI-166 I [127] Abbreviation: D/C, discontinuation.…”

Weak links: Advancing target‐based drug discovery by identifying the most vulnerable targets

“…While small molecules can have diverse mechanisms of enzyme inhibition or agonism, CRISPRi only mimics the effect imposed by a noncompetitive inhibitor 64 . For example, GSK‐286 is a preclinical compound that blocks cholesterol catabolism in Mtb by functioning as an agonist of the adenylyl cyclase rv1625c 65 . Second, the depletion of a target is not the same as the inhibition of its functional activity by a small molecule 66 .…”

“…64 For example, GSK-286 is a preclinical compound that blocks cholesterol catabolism in Mtb by functioning as an agonist of the adenylyl cyclase rv1625c. 65 Second, the depletion of a target is not the same as the inhibition of its functional activity by a small molecule. 66 For example, although a small molecule may selectively inhibit the enzymatic but not scaffolding function of an enzyme, CRISPRi will necessarily inhibit both.…”