In vitro potency of 2-(((2-hydroxyphenyl)amino) methylene)-5,5-dimethylcyclohexane-1,3-dione against drug-resistant and nonreplicating persisters of Mycobacterium tuberculosis

J Glob Antimicrob Resist. 2021 Mar 28:S2213-7165(21)00081-3. doi: 10.1016/j.jgar.2021.03.015. Online ahead of print.


OBJECTIVES: New antituberculosis agents active on drug-resistant and nonreplicating tubercle bacilli remain an unmet medical obligation. We, therefore, evaluated a previously identified hit 2-(((2-hydroxyphenyl)amino) methylene)-5,5-dimethylcyclohexane-1,3-dione (PAMCHD) against a panel of clinical Mycobacterium tuberculosis isolates including multidrug-resistant (MDR) strains and against nonreplicating drug-tolerant persisters of M. tuberculosis H37Rv.

METHODS: potential against drug-resistant isolates of M.tuberculosis was investigated by broth dilution assay. CFU enumeration was done to determine the activity of PAMCHD against five kinds of dormant bacilli.

RESULTS: No significant difference in MICs of PAMCHD was observed against M .tuberculosis H37Rv (2.5-5 µg/mL) and eight drug-susceptible strains (1.25-5 µg/mL) as well as drug-resistant strains including six isoniazid (INH)- (2.5-10 µg/mL) one INH+ ethambutol (EMB)- (5 µg/mL), one RIF+ EMB- (5 µg/mL) resistant strains and three MDR strains. (2.5-10 µg/mL). Thereby, PAMCHD maintains its activity against all the kinds of clinical strains, especially against MDR strains. With respect to drug-tolerant persisters, INH and RIF killed 0.5 and 5.0 log10 CFUs of nonreplicating persisters developed by hypoxia and 1.5 and 2.5 log10 CFUs developed by nutrient starvation respectively at 64X of their respective MIC against actively dividing cultures. Contrary to this, PAMCHD sterilized persister cultures developed by hypoxia (killed 6.5 log10 CFU) or starvation (killed 7.5 log10 CFU). PAMCHD sterilized RIF tolerant (with tolerance level up to 100µg/mL of RIF) 100-day old static persisters at 64X MIC while moxifloxacin (MOX) was able to kill only 1.0 log10 CFU of these persisters at 64X MIC corresponding to MXF.

CONCLUSION: PAMCHD offers significant potential against MDR-TB and exhibits notable potency against nonreplicating drug-tolerant M. tuberculosis persisters. These findings warrant further studies on PAMCHD for further TB drug development.

PMID:33789204 | DOI:10.1016/j.jgar.2021.03.015