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

Autor: Rather MA; Clinical Microbiology and PK/PD Division, CSIR - Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, India., Bhat ZS; Clinical Microbiology and PK/PD Division, CSIR - Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, India; Academy of Scientific and Innovative Research, CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi 180001, Jammu & Kashmir, India., Lone AM; Medicinal Chemistry Division, CSIR - Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, India., Maqbool M; Clinical Microbiology and PK/PD Division, CSIR - Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, India., Bhat BA; Medicinal Chemistry Division, CSIR - Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, India., Ahmad Z; Clinical Microbiology and PK/PD Division, CSIR - Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, India; Academy of Scientific and Innovative Research, CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi 180001, Jammu & Kashmir, India. Electronic address: zahoorap@iiim.ac.in.
Jazyk: angličtina
Zdroj: Journal of global antimicrobial resistance [J Glob Antimicrob Resist] 2021 Jun; Vol. 25, pp. 202-208. Date of Electronic Publication: 2021 Mar 28.
DOI: 10.1016/j.jgar.2021.03.015
Abstrakt: Objectives: 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.
Methods: 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.
Results: 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 log 10 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.
Conclusion: 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.
(Copyright © 2021 International Society for Antimicrobial Chemotherapy. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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