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In vitro bactericidal activity of 3-Cinnamoyl-4-hydroxy-6-methyl-2-pyrone (CHP) against drug-susceptible, resistant and tolerant isolates of Mycobacterium tuberculosis.

Abstract

OBJECTIVES

Tuberculosis (TB) poses a serious global threat to human population. New bactericidal agents that can shorten treatment duration and target drug resistance still remain a top priority in TB drug discovery. The objective of this study was to investigate the bactericidal potential of 3-Cinnamoyl-4-hydroxy-6-methyl-2-pyrone (CHP) against drug susceptible, resistant clinical isolates and tolerant Mycobacterium tuberculosis.

METHODS

Minimum bactericidal concentration (MBC) was determined by colony forming unit (CFU) enumeration; kill curve analysis was done at different concentrations spanning over 16 days; drug combination studies with antituberculosis drugs were done to investigate possible synergy; potential against drug resistant isolates of M.tuberculosis was done by broth dilution assay; CFU enumeration was done to determine its activity against nutrient starved drug tolerants; and its feasibility for oral administration was tested by serum inhibitory titre.

RESULTS

a) CHP displayed bactericidal activity with MBC of 4 µg/mL against M.tuberculosis H37Rv, Kill curve analysis exhibited a biphasic pattern of killing; b) CHP showed synergy with rifampicin, isoniazid and amikacin but was indifferent towards ethambutol and levofloxacin, c) CHP retained its full activity against drug susceptible, monoresistant and multidrug resistant (MDR) clinical isolates; d) CHP showed very strong bactericidal activity against non dividing drug tolerant M.tuberculosis that on comparison was highly superior to rifampicin. Furthermore, CHP significantly improved the bactericidal activity of rifampicin and isoniazid in combination study; e) Serum inhibitory titre in mice depicted its high oral bioavailability.

CONCLUSION

Our results show strong bactericidal potential of CHP against M.tuberculosis that warrant its immediate mechanistic, pharmacokinetic and pharmacodynamic studies.

Authors+Show Affiliations

Clinical Microbiology and PK/PD Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, Jammu & Kashmir 190005, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, 180001, India.Clinical Microbiology and PK/PD Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, Jammu & Kashmir 190005, India.Medicinal chemistry division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, Jammu & Kashmir 190005, India.Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, 180001, India.Clinical Microbiology and PK/PD Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, Jammu & Kashmir 190005, India.Medicinal chemistry division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, Jammu & Kashmir 190005, India.State Training Demonstration Centre and Intermediate Reference Lab (STDC-IRL), Dalgate Srinagar Kashmir, 190001, India.State Training Demonstration Centre and Intermediate Reference Lab (STDC-IRL), Dalgate Srinagar Kashmir, 190001, India.Clinical Microbiology and PK/PD Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, Jammu & Kashmir 190005, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, 180001, India. Electronic address: zahoorap@iiim.ac.in.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31809940

Citation

Bhat, Zubair Shanib, et al. "In Vitro Bactericidal Activity of 3-Cinnamoyl-4-hydroxy-6-methyl-2-pyrone (CHP) Against Drug-susceptible, Resistant and Tolerant Isolates of Mycobacterium Tuberculosis." Journal of Global Antimicrobial Resistance, 2019.
Bhat ZS, Rather MA, Lah HU, et al. In vitro bactericidal activity of 3-Cinnamoyl-4-hydroxy-6-methyl-2-pyrone (CHP) against drug-susceptible, resistant and tolerant isolates of Mycobacterium tuberculosis. J Glob Antimicrob Resist. 2019.
Bhat, Z. S., Rather, M. A., Lah, H. U., Hussain, A., Maqbool, M., Yousuf, S. K., ... Ahmad, Z. (2019). In vitro bactericidal activity of 3-Cinnamoyl-4-hydroxy-6-methyl-2-pyrone (CHP) against drug-susceptible, resistant and tolerant isolates of Mycobacterium tuberculosis. Journal of Global Antimicrobial Resistance, doi:10.1016/j.jgar.2019.11.018.
Bhat ZS, et al. In Vitro Bactericidal Activity of 3-Cinnamoyl-4-hydroxy-6-methyl-2-pyrone (CHP) Against Drug-susceptible, Resistant and Tolerant Isolates of Mycobacterium Tuberculosis. J Glob Antimicrob Resist. 2019 Dec 3; PubMed PMID: 31809940.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro bactericidal activity of 3-Cinnamoyl-4-hydroxy-6-methyl-2-pyrone (CHP) against drug-susceptible, resistant and tolerant isolates of Mycobacterium tuberculosis. AU - Bhat,Zubair Shanib, AU - Rather,Muzafar Ahmad, AU - Lah,Hafiz Ul, AU - Hussain,Aehtesham, AU - Maqbool,Mubashir, AU - Yousuf,Syed Khalid, AU - Jabeen,Zuhra, AU - Wani,Mushtaq Ahmad, AU - Ahmad,Zahoor, Y1 - 2019/12/03/ PY - 2019/05/30/received PY - 2019/10/06/revised PY - 2019/11/25/accepted PY - 2019/12/7/entrez PY - 2019/12/7/pubmed PY - 2019/12/7/medline KW - Antituberculosis activity KW - Cinnamoyl pyrones KW - Dormant/tolerant bacilli KW - Mycobacterium tuberculosis, MDR-TB KW - Synergism KW - oral bioavalibility JF - Journal of global antimicrobial resistance JO - J Glob Antimicrob Resist N2 - OBJECTIVES: Tuberculosis (TB) poses a serious global threat to human population. New bactericidal agents that can shorten treatment duration and target drug resistance still remain a top priority in TB drug discovery. The objective of this study was to investigate the bactericidal potential of 3-Cinnamoyl-4-hydroxy-6-methyl-2-pyrone (CHP) against drug susceptible, resistant clinical isolates and tolerant Mycobacterium tuberculosis. METHODS: Minimum bactericidal concentration (MBC) was determined by colony forming unit (CFU) enumeration; kill curve analysis was done at different concentrations spanning over 16 days; drug combination studies with antituberculosis drugs were done to investigate possible synergy; potential against drug resistant isolates of M.tuberculosis was done by broth dilution assay; CFU enumeration was done to determine its activity against nutrient starved drug tolerants; and its feasibility for oral administration was tested by serum inhibitory titre. RESULTS: a) CHP displayed bactericidal activity with MBC of 4 µg/mL against M.tuberculosis H37Rv, Kill curve analysis exhibited a biphasic pattern of killing; b) CHP showed synergy with rifampicin, isoniazid and amikacin but was indifferent towards ethambutol and levofloxacin, c) CHP retained its full activity against drug susceptible, monoresistant and multidrug resistant (MDR) clinical isolates; d) CHP showed very strong bactericidal activity against non dividing drug tolerant M.tuberculosis that on comparison was highly superior to rifampicin. Furthermore, CHP significantly improved the bactericidal activity of rifampicin and isoniazid in combination study; e) Serum inhibitory titre in mice depicted its high oral bioavailability. CONCLUSION: Our results show strong bactericidal potential of CHP against M.tuberculosis that warrant its immediate mechanistic, pharmacokinetic and pharmacodynamic studies. SN - 2213-7173 UR - https://www.unboundmedicine.com/medline/citation/31809940/In_vitro_bactericidal_activity_of_3-Cinnamoyl-4-hydroxy-6-methyl-2-pyrone_(CHP)_against_drug-susceptible,_resistant_and_tolerant_isolates_of_Mycobacterium_tuberculosis L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-7165(19)30311-X DB - PRIME DP - Unbound Medicine ER -