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Abstract Fluoroquinolone resistance is a major challenge in treating Multidrug-Resistant Tuberculosis globally. The GenoType MTBDRsl Ver 2.0, endorsed by the WHO, was used to characterize fluoroquinolone resistance. The fluoroquinolone resistance rates in the MDR-TB, Rifampicin-Resistant TB, and non-MDR-TB were 33%, 16.5%, and 5.4%, respectively. The most common mutation found in fluoroquinolone-resistant isolates was D94G (49.5%) in the gyrA gene. Of the 150 MDR-TB isolates, the prevalence of Extensively Drug-Resistant Tuberculosis and pre-XDR-TB was 1.33% and 30%, respectively. Among the 139 RR-TB isolates, pre-XDR-TB prevalence was 15.8%. The fluoroquinolone resistance rates were 5.12% among the 1230 isoniazid-monoresistant isolates. The study found that MDR-TB and RR-TB have higher risk of fluoroquinolone resistance than non-MDR tuberculosis. Rifampicin-resistant isolates with a mutation at codon S450L have a higher risk (RR = 12.96; 95%CI: 8.34–20.13) of developing fluoroquinolone resistance than isolates with mutations at other codons in the rpoB gene. Isoniazid-resistant isolates with a mutation at codon S315T have a higher risk (RR = 2.09; 95%CI: 1.25–3.50) of developing fluoroquinolone resistance. The study concludes that rapid diagnosis of fluoroquinolone resistance before starting treatment is urgently needed to prevent the spread and increase of resistance and to achieve better treatment outcomes in areas where it is higher.

Aim: We designed and synthesized a series of compounds with a 3,5-disubstituted pyridine moiety and evaluated them against Mycobacterium tuberculosis (Mtb) and drug-resistant Mtb clinical isolates. Methodology: A library of 3,5-disubstituted pyridine was synthesized. The compounds were screened for activity against M. tuberculosis H37Rv. The optimal substitutions needed for the activity were identified through structure-activity relationship (SAR) studies. Results: From the screening studies, compounds 24 and 26 were identified as potent members of this series with Minimum Inhibitory Concentration (MIC) of 1.56 μg/ml against M. tuberculosis H37Rv. These compounds did not show any inhibition against a panel of ESKAPE pathogens at >50 μg/ml indicating their selective killing of M. tuberculosis H37Rv. Importantly, compound 24 showed a selectivity index of 54.64 against CHO-K1 and 78.26 against VERO cell lines, while compound 26 showed a selectivity index of 108.5 against CHO-K1 and 63.2 against VERO cell lines, respectively. Compound 24 formed a stable complex with the target protein DprE1 with predicted binding energy -8.73 kcal/mol and inhibited multidrug-resistant clinical isolate of M. tuberculosis at 6.25 μg/ml. Conclusion: This study identified the 3,5-disubstituted pyridine derivative 24 with potent antituberculosis activity and can be taken forward to generate new preclinical candidate.

Three new 22-membered polyol macrolides, dactylides A-C (1-3), were isolated from Dactylosporangium aurantiacum ATCC 23491 employing repeated chromatographic separations, and their structures were established based on detailed analysis of NMR and MS data. The relative configurations at the stereocenters were established via vicinal 1 H- 1 H coupling constants, NOE correlations, and by application of Kishi's universal NMR database. In order to get insights into the biosynthetic pathway of 1-3, the genome sequence of the producer strain D. aurantiacum was obtained and the putative biosynthetic gene cluster encoding their biosynthesis was identified through bioinformatic analysis using antiSMASH. Compounds 1-3 showed significant in-vitro antimycobacterial and cytotoxic activity., (© 2023. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

Background & Objectives: Drug-resistant tuberculosis (TB) jeopardizes the treatment process with poor outcomes. Efflux pumps (EPs) belonging to the ABC transporter family in Mycobacterium tuberculosis confer resistance to rifampicin (RMP) besides genetic mutations thus serving as a target for a potential adjunct therapeutic inhibitory molecule. Rv1218c is one such pump that was previously reported to be active in multidrug-resistant TB clinical isolates., Methods: In this study, the inhibition potential of Rv1218c-EP was tested on 8 molecules that were shortlisted by in silico methods. These molecules were subjected to the minimum inhibitory concentration (MIC) determination, checkerboard drug combination assay, ethidium bromide-DNA binding assay, and in vitro and ex vivo cytotoxicity assay., Results: Based on the outcome of the study, two molecules dodecanoic acid (DA) and palmitic acid (PA) were found to be potential enough to decrease the MIC of RMP by 8 to 1000 folds against multidrug-resistant clinical isolates and Rv1218c expressing recombinant Mycobacterium smegmatis., Interpretation & Conclusions: These molecules were also found to reduce the time taken by RMP to kill these drug-resistant Mycobacteria to 48 h, unlike control isolates that survived more than 240 h of RMP exposure. The functional concentration of both molecules was non-toxic to the epithelial and blood mononuclear cells. With further comprehensive scientific validation, PA and DA could be recommended as adjunct therapeutic molecules with first-line anti-TB drugs to treat drug-resistant TB.

Ethnopharmacological Relevance: The multidrug-resistant (MDR) pathogen, Mycobacterium tuberculosis, still remains as one of the major threat to mankind, despite the availability of a live attenuated vaccine and effective antibiotics. Marine microalgae, at all times, act as a key resource for valuable therapeutic compounds with limited side effects., Aim of the Study: The present explorative attempt is to isolate the biomolecules of pharmacological importance from the marine microalgae, Chlorella vulgaris, and to evaluate its effect on the ever dreadful disease, Tuberculosis. The study is also aimed to develop an economically feasible methodology for by-products extraction from microalgae., Materials and Methods: Fatty acids-carotenoid complexes (FACC), namely, FACC-1 (red oil) and FACC-2 (brown oil) were isolated, in addition to lipid and lutein from the Chlorella Growth Factor (CGF, a protein fraction enriched with vitamins, minerals and carbohydrates)-extracted spent biomass through column chromatography., Results: FACC-1 is a complex of fatty acids such as oleic and linoleic acids, and carotenoids such as canthaxanthin and neoxanthin. FACC-2 is a complex of oleic, linoleic and linolenic acids and carotenoids (cryptoxanthin and echinenone). Initial screening for evaluation of minimum bactericidal concentration (MBC) of FACC-1 and -2 was performed against Mycobacterium tuberculosis strains such as H37Rv, SHRE sensitive clinical isolate and SHRE resistant clinical isolate. MBC was noted at 10 μg/mL by FACC-1 and at 5 μg/mL by FACC-2, determined using colony forming and Lucipherase Reporter Mycobacteriophages (LRP) assay. Testing in the PAN sensitive isolates indicated that the MBC was noted at 5 μg/mL by FACC-1 and at 2.5 μg/mL by FACC-2. Complete inhibition (100%) was observed at 100 μg/mL by FACC-1 and at 50 μg/mL by FACC-2. Testing of FACC-1 and FACC-2 individually as well as in combination on two different types of MDR strains confirmed the efficacy of the algal oils, wherein in MDR-strain 1, FACC-1 revealed 50% inhibition at 10 μg/mL, while FACC-2 exhibited the same at 5 μg/mL. Conversely, in the case of MDR strain-2, MBC of FACC-1 was at 500 μg/mL and MBCof FACC-2 to be at 250 μg/mL. No significant synergistic effect was observed on combining both the oils., Conclusion: The study signifies the development of a potent therapeutic agent comprising of a complex of anti-TB agent (fatty acids) and antioxidants (carotenoids) from the CGF-extracted spent biomass of C. vulgaris., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: In recent times, heterocyclic chemotypes are being explored for the development of new antimycobacterials that target the drug-resistant tuberculosis. Here, we are disclosing the 5-substitued 2-mercapto-1,3,4-oxadiazoles as potent antitubercular agents., Methodology: A small library of 2-mercapto-1,3,4-oxadiazoles was synthesized using various acids. The compounds were evaluated for antituberculosis activity against M. tuberculosis H37Rv., Results: Compound 8j was identified as antitubercular lead with MIC of 0.6 μg/ml against M. tuberculosis H37Rv. This compound was nontoxic to CHO-K1 cells and showed selectivity index of 39. Of note, 8j showed antitubercular activity against pre-extensively drug-resistant clinical isolate of Mycobacterium with MIC of 2 μg/ml., Conclusion: This study provides potent antitubercular agent which can be further optimized to discover novel antibiotics.