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 2019JG
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.
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.
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.
Our results show strong bactericidal potential of CHP against M.tuberculosis that warrant its immediate mechanistic, pharmacokinetic and pharmacodynamic studies.