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
ABSTRACT: 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 tuber...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-06-01
|
| Series: | Journal of Global Antimicrobial Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213716521000813 |
| _version_ | 1818865385400696832 |
|---|---|
| author | Muzafar Ahmad Rather Zubair Shanib Bhat Ali Mohd Lone Mubashir Maqbool Bilal Ahmad Bhat Zahoor Ahmad |
| author_facet | Muzafar Ahmad Rather Zubair Shanib Bhat Ali Mohd Lone Mubashir Maqbool Bilal Ahmad Bhat Zahoor Ahmad |
| author_sort | Muzafar Ahmad Rather |
| collection | DOAJ |
| description | ABSTRACT: 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 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. 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. |
| first_indexed | 2024-12-19T10:46:43Z |
| format | Article |
| id | doaj.art-2ba2e36789b142ac9c7f02903c79a089 |
| institution | Directory Open Access Journal |
| issn | 2213-7165 |
| language | English |
| last_indexed | 2024-12-19T10:46:43Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Global Antimicrobial Resistance |
| spelling | doaj.art-2ba2e36789b142ac9c7f02903c79a0892022-12-21T20:25:13ZengElsevierJournal of Global Antimicrobial Resistance2213-71652021-06-0125202208In vitro potency of 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione against drug-resistant and non-replicating persisters of Mycobacterium tuberculosisMuzafar Ahmad Rather0Zubair Shanib Bhat1Ali Mohd Lone2Mubashir Maqbool3Bilal Ahmad Bhat4Zahoor Ahmad5Clinical Microbiology and PK/PD Division, CSIR – Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, IndiaClinical 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, IndiaMedicinal Chemistry Division, CSIR – Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, IndiaClinical Microbiology and PK/PD Division, CSIR – Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, IndiaMedicinal Chemistry Division, CSIR – Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, India; Corresponding author: Mailing address: Clinical Microbiology and PK/PD Division, Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, India, Tel.: +91 99 0659 3222; fax: +91 194 244 1331 (Z. Ahmad).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; Corresponding author: Mailing address: Clinical Microbiology and PK/PD Division, Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, Jammu & Kashmir, India, Tel.: +91 99 0659 3222; fax: +91 194 244 1331 (Z. Ahmad).ABSTRACT: 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 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. 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.http://www.sciencedirect.com/science/article/pii/S2213716521000813PAMCHDMultidrug-resistant TBMycobacterium tuberculosisResistanceTolerancePersistence |
| spellingShingle | Muzafar Ahmad Rather Zubair Shanib Bhat Ali Mohd Lone Mubashir Maqbool Bilal Ahmad Bhat Zahoor Ahmad 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 Journal of Global Antimicrobial Resistance PAMCHD Multidrug-resistant TB Mycobacterium tuberculosis Resistance Tolerance Persistence |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | PAMCHD Multidrug-resistant TB Mycobacterium tuberculosis Resistance Tolerance Persistence |
| url | http://www.sciencedirect.com/science/article/pii/S2213716521000813 |
| work_keys_str_mv | AT muzafarahmadrather invitropotencyof22hydroxyphenylaminomethylene55dimethylcyclohexane13dioneagainstdrugresistantandnonreplicatingpersistersofmycobacteriumtuberculosis AT zubairshanibbhat invitropotencyof22hydroxyphenylaminomethylene55dimethylcyclohexane13dioneagainstdrugresistantandnonreplicatingpersistersofmycobacteriumtuberculosis AT alimohdlone invitropotencyof22hydroxyphenylaminomethylene55dimethylcyclohexane13dioneagainstdrugresistantandnonreplicatingpersistersofmycobacteriumtuberculosis AT mubashirmaqbool invitropotencyof22hydroxyphenylaminomethylene55dimethylcyclohexane13dioneagainstdrugresistantandnonreplicatingpersistersofmycobacteriumtuberculosis AT bilalahmadbhat invitropotencyof22hydroxyphenylaminomethylene55dimethylcyclohexane13dioneagainstdrugresistantandnonreplicatingpersistersofmycobacteriumtuberculosis AT zahoorahmad invitropotencyof22hydroxyphenylaminomethylene55dimethylcyclohexane13dioneagainstdrugresistantandnonreplicatingpersistersofmycobacteriumtuberculosis |