Abstract
Purpose: To investigate the anti-tuberculosis potential of twelve commercially available pyridone analogues against Mycobacterium tuberculosis H37Rv strain.Methods: Twelve commercially available pyridone-based compounds were screened against M. tuberculosis H37Rv using different susceptibility tests. The most active or lead compound was further evaluated in detail for its anti-tuberculosis (anti-TB) potential. Kill kinetics was used to determine the dynamics of its anti-TB activity in vitro.Results: Compounds d, j and k were potent against M. tuberculosis H37Rv, with minimum inhibitory concentrations (MICs) of 10, 5 and 10 μg/mL, respectively. The standard anti-TB drugs used in this study (positive control drugs) demonstrated MIC of 2.5 μg/mL. The anti-TB effect of compound j was comparable with those of the standard drugs (RIF, LVX, AMK, EMB and INH). The minimum bactericidal concentration (MBC) of compound j was 10 μg/mL. It produced an MIC of 5 μg/mL in agar proportion method (APM). However, its MIC in Middlebrook 7H9 broth supplemented with 10 % fetal bovine serum (FBS) and 4 % bovine serum albumin (BSA) increased 4- and 8-fold, respectively. The bactericidal effect of compound j was time- and concentration-dependent at dilutions above 2x MIC. Combination of compound j with RIF, LVX or AMK exhibited fractional inhibitory concentration index (ΣFIC) of 1, indicative of additive drug-drug interactions. However, combination with INH or EMB produced a ΣFIC of 2. None of the tested drug combinations was antagonistic.Conclusion: Compound j exhibits potent time- and concentration-dependent antimicrobial effect against M. tuberculosis H37Rv. Thus, it may be suitable as an adjunct to current treatment of drug sensitive and drug-resistant TB.
 Keywords: Tuberculosis, Mycobacterium tuberculosis, Pyridone analogs, Antimicrobial activity, Antibiotics
Highlights
Tuberculosis (TB) is a chronic bacterial infectious disease caused by Mycobacterium tuberculosis
Work on TB drug development is focused on the identification of new chemical moieties and therapeutic scaffolds that can sufficiently improve the pharmacological effects of the drugs [3]
This study investigated the inhibitory effects of pyridone-based compounds on M. tuberculosis H37Rv
Summary
Tuberculosis (TB) is a chronic bacterial infectious disease caused by Mycobacterium tuberculosis. Minimum inhibitory concentration (MIC) of the lead compound and INH were determined in Middlebrook 7H9 broth supplemented with 4 % BSA or 10 % FBS or without protein supplementation. In vitro drug-drug interaction studies on the first or second line anti-TB drugs were evaluated using standard method with slight modification [4].The test compound was mixed with INH, RIF, EMB, LVX or AMK at 16-fold serial dilution of their respective MICs in 96-well plates. Mycobacterium tuberculosis cells in logarithmic growth phase (1 x 105 CFU/mL) were challenged with the test compound based on its MIC (16-fold dilution) for 16 days in 15 mL falcon tubes. Where ΣFIC ≤ 0.5, 0.5 - 4.0 and ≥ 4.0 reflect synergistic, antagonistic and indifferent or additive interaction, respectively [13,14]
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