Abstract
New antituberculosis agents active against drug-resistant and non-replicating tubercle bacilli are required. We evaluated a previously identified hit, 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (PAMCHD), against several clinical Mycobacterium tuberculosis isolates, including multidrug-resistant (MDR) strains and non-replicating drug-tolerant persisters of M. tuberculosis H37Rv. PAMCHD's potential against drug-resistant M. tuberculosis was investigated by broth microdilution. CFU enumeration was performed to determine PAMCHD's activity against five types of dormant bacilli. No significant differences in MICs of PAMCHD were 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)-resistant (2.5-10 µg/mL), one INH+ethambutol (EMB)-resistant (5 µg/mL), one rifampicin (RIF)+EMB-resistant (5 µg/mL) and three MDR (2.5-10 µg/mL) strains. Thus, PAMCHD maintains activity against all kinds of clinical strains, especially MDR. Regarding drug-tolerant persisters, INH and RIF killed, respectively, 0.5 and 5.0 log10 CFU of non-replicating persisters developed by hypoxia and 1.5 and 2.5 log10 CFU developed by nutrient starvation at 64×of their respective MIC against actively dividing cultures. In contrast, PAMCHD sterilised persister cultures developed by hypoxia (killed 6.5 log10 CFU) or starvation (killed 7.5 log10 CFU). PAMCHD sterilised RIF-tolerant (tolerance level up to 100 µg/mL of RIF) 100-day-old static persisters at 64×MIC, while moxifloxacin killed only 1.0 log10 CFU of these persisters at 64×MIC. PAMCHD offers significant potential against MDR-TB and exhibits notable potency against non-replicating drug-tolerant M. tuberculosis persisters. These findings warrant further studies of PAMCHD for further anti-TB drug development.
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