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

Novel anti-tuberculosis drugs are essential to manage drug resistant tuberculosis, caused by the notorious pathogen Mycobacterium tuberculosis. We recently reported the antimycobacterial activity of chrysomycin A in vitro and in infected macrophages. In this study, we report that the molecule inhibits the growth of drug resistant clinical strains of Mycobacterium tuberculosis and acts in synergy with anti-TB drugs such as ethambutol, ciprofloxacin and novobiocin. In pursuit of its mechanism of action, it was found that chrysomycin A renders bactericidal activity by interacting with DNA at specific sequences and by inhibiting topoisomerase I activity of Mycobacterium tuberculosis. It also exhibits weak inhibition of gyrase enzyme of the pathogen.

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In Vitro Synergism Testing of Three Antimicrobial Agents against Multidrug- Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis by Checkerboard Method

Journal of Molecular Pharmaceutics & Organic Process Research ◽

10.4172/2329-9053.1000123 ◽

2015 ◽

Vol 03 (01) ◽

Author(s):

Liping Yan Linlin Zhang

Keyword(s):

Mycobacterium Tuberculosis ◽

Antimicrobial Agents ◽

Multidrug Resistant ◽

Drug Resistant ◽

Extensively Drug Resistant

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Comparison of In Vitro Activity and MIC Distributions between the Novel Oxazolidinone Delpazolid and Linezolid against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis in China

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00165-18 ◽

2018 ◽

Vol 62 (8) ◽

Cited By ~ 18

Author(s):

Zhaojing Zong ◽

Wei Jing ◽

Jin Shi ◽

Shu'an Wen ◽

Tingting Zhang ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Novel Mutation ◽

Multidrug Resistant ◽

23S Rrna ◽

Drug Resistant ◽

Content Type ◽

Extensively Drug Resistant ◽

Significant Difference ◽

Mdr Tb

ABSTRACT Oxazolidinones are efficacious in treating mycobacterial infections, including tuberculosis (TB) caused by drug-resistant Mycobacterium tuberculosis. In this study, we compared the in vitro activities and MIC distributions of delpazolid, a novel oxazolidinone, and linezolid against multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) in China. Additionally, genetic mutations in 23S rRNA, rplC, and rplD genes were analyzed to reveal potential mechanisms underlying the observed oxazolidinone resistance. A total of 240 M. tuberculosis isolates were included in this study, including 120 MDR-TB isolates and 120 XDR-TB isolates. Overall, linezolid and delpazolid MIC90 values for M. tuberculosis isolates were 0.25 mg/liter and 0.5 mg/liter, respectively. Based on visual inspection, we tentatively set epidemiological cutoff (ECOFF) values for MIC determinations for linezolid and delpazolid at 1.0 mg/liter and 2.0 mg/liter, respectively. Although no significant difference in resistance rates was observed between linezolid and delpazolid among XDR-TB isolates (P > 0.05), statistical analysis revealed a significantly greater proportion of linezolid-resistant isolates than delpazolid-resistant isolates within the MDR-TB group (P = 0.036). Seven (53.85%) of 13 linezolid-resistant isolates were found to harbor mutations within the three target genes. Additionally, 1 isolate exhibited an amino acid substitution (Arg126His) within the protein encoded by rplD that contributed to high-level resistance to linezolid (MIC of >16 mg/liter), compared to a delpazolid MIC of 0.25. In conclusion, in vitro susceptibility testing revealed that delpazolid antibacterial activity was comparable to that of linezolid. A novel mutation within rplD that endowed M. tuberculosis with linezolid, but not delpazolid, resistance was identified.

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In vitro synergistic interactions of oleanolic acid in combination with isoniazid, rifampicin or ethambutol against Mycobacterium tuberculosis

Journal of Medical Microbiology ◽

10.1099/jmm.0.014837-0 ◽

2010 ◽

Vol 59 (5) ◽

pp. 567-572 ◽

Cited By ~ 20

Author(s):

Fa Ge ◽

Fanli Zeng ◽

Siguo Liu ◽

Na Guo ◽

Haiqing Ye ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Oleanolic Acid ◽

Antimycobacterial Activity ◽

Vero Cells ◽

Drug Resistant ◽

Synergistic Interactions ◽

Combination Treatments ◽

Low Cytotoxicity ◽

Drug Resistant Strains

Reports have shown that oleanolic acid (OA), a triterpenoid, exists widely in food, medicinal herbs and other plants, and that it has antimycobacterial activity against the Mycobacterium tuberculosis strain H37Rv (ATCC 27294). In this study it was found that OA had antimycobacterial properties against eight clinical isolates of M. tuberculosis and that the MICs of OA against drug-sensitive and drug-resistant isolates were 50–100 and 100–200 μg ml−1, respectively. The combination of OA with isoniazid (INH), rifampicin (RMP) or ethambutol (EMB) showed favourable synergistic antimycobacterial effects against six drug-resistant strains, with fractional inhibitory concentration indices of 0.121–0.347, 0.113–0.168 and 0.093–0.266, respectively. The combination treatments of OA/INH, OA/RMP and OA/EMB displayed either a synergistic interaction or did not show any interaction against two drug-sensitive strains. No antagonism resulting from the OA/INH, OA/RMP or OA/EMB combination was observed for any of the strains tested. OA exhibited a relatively low cytotoxicity in Vero cells. These results indicate that OA may serve as a promising lead compound for future antimycobacterial drug development.

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Antimicrobial Peptide against Mycobacterium Tuberculosis That Activates Autophagy Is an Effective Treatment for Tuberculosis

Pharmaceutics ◽

10.3390/pharmaceutics12111071 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1071

Author(s):

Erika A. Peláez Coyotl ◽

Jacqueline Barrios Palacios ◽

Gabriel Muciño ◽

Daniel Moreno-Blas ◽

Miguel Costas ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Antimicrobial Peptide ◽

Low Dose ◽

Antibiotic Activity ◽

Drug Resistant ◽

Mice Model ◽

Therapeutic Modalities ◽

Mdr Tb ◽

A Cell

Mycobacterium tuberculosis (MTB) is the principal cause of human tuberculosis (TB), which is a serious health problem worldwide. The development of innovative therapeutic modalities to treat TB is mainly due to the emergence of multi drug resistant (MDR) TB. Autophagy is a cell-host defense process. Previous studies have reported that autophagy-activating agents eliminate intracellular MDR MTB. Thus, combining a direct antibiotic activity against circulating bacteria with autophagy activation to eliminate bacteria residing inside cells could treat MDR TB. We show that the synthetic peptide, IP-1 (KFLNRFWHWLQLKPGQPMY), induced autophagy in HEK293T cells and macrophages at a low dose (10 μM), while increasing the dose (50 μM) induced cell death; IP-1 induced the secretion of TNFα in macrophages and killed Mtb at a dose where macrophages are not killed by IP-1. Moreover, IP-1 showed significant therapeutic activity in a mice model of progressive pulmonary TB. In terms of the mechanism of action, IP-1 sequesters ATP in vitro and inside living cells. Thus, IP-1 is the first antimicrobial peptide that eliminates MDR MTB infection by combining four activities: reducing ATP levels, bactericidal activity, autophagy activation, and TNFα secretion.

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Activity of pyrazinamide in a murine model against Mycobacterium tuberculosis isolates with various levels of in vitro susceptibility.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.1.14 ◽

1996 ◽

Vol 40 (1) ◽

pp. 14-16 ◽

Cited By ~ 16

Author(s):

S P Klemens ◽

C A Sharpe ◽

M H Cynamon

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Efficacy ◽

Viable Cell ◽

Test System ◽

Infection Model ◽

Drug Resistant ◽

In Vitro Susceptibility ◽

Cell Counts ◽

Treatment Of Infection

The activity of pyrazinamide (PZA) against eight isolates of Mycobacterium tuberculosis in a murine infection model was evaluated. M. tuberculosis isolates with various degrees of in vitro susceptibility to PZA (MIC range, 32 to > 2,048 micrograms/ml) were used. Four-week-old female mice were infected intravenously with approximately 10(7) viable M. tuberculosis organisms. PZA at 150 mg/kg of body weight was started 1 day postinfection and given 5 days/week for 4 weeks. Infected but untreated mice were compared with PZA-treated mice. Mice were sacrificed at the completion of the treatment period, and viable cell counts were determined from homogenates of spleens and right lungs. PZA had activity in the murine test system against M. tuberculosis isolates for which the MICs were < or = 256 micrograms/ml. However, there was an inconsistent correlation between the absolute MICs and the reductions in organ viable cell counts. Studies with drug-resistant M. tuberculosis isolates with an isogenic background would improve evaluation of drug efficacy in the murine test system. Further evaluation of antimycobacterial agents against monodrug-resistant isolates will provide data that will be useful for development of algorithms for treatment of infection with drug-resistant organisms.

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In Vitro Antimycobacterial Activities of 2′-Monosubstituted Isonicotinohydrazides and Their Cyanoborane Adducts

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.2.294-299.2002 ◽

2002 ◽

Vol 46 (2) ◽

pp. 294-299 ◽

Cited By ~ 46

Author(s):

Rosanna Maccari ◽

Rosaria Ottanà ◽

Francesca Monforte ◽

Maria Gabriella Vigorita

Keyword(s):

Mycobacterium Tuberculosis ◽

High Activity ◽

Culture Medium ◽

Antimycobacterial Activity ◽

Drug Resistant ◽

Good Activity ◽

Sodium Cyanoborohydride ◽

Low Cytotoxicity ◽

Safety Indices

ABSTRACT As a result of our search for new isoniazid derivatives with extended spectra of activity, we evaluated the in vitro antimycobacterial activities of isonicotinohydrazides (compounds 2) and their cyanoborane adducts (compounds 3), both obtained by the reaction of isonicotinoylhydrazones (compounds 1) with sodium cyanoborohydride. Most of the tested compounds displayed moderate to high activity against Mycobacterium tuberculosis H37Rv, with MICs ranging from 0.2 to 12.5 μg/ml. In particular, some hydrazides showed activity similar to that of rifampin (MIC = 0.2 μg/ml) and rather low cytotoxicity, so that they were generally shown to possess high safety indices. In contrast, the coordination to a cyanoborane (BH2CN) group (compounds 3) in general brought about a decrease in antimycobacterial activity, while cytotoxicity increased. Interestingly, selected compounds 1 to 3, mostly hydrazides (compounds 2), were effective in killing M. tuberculosis growing within macrophages at concentrations in culture medium which were much lower than the corresponding MICs. These compounds also displayed good activity against drug-resistant M. tuberculosis strains.

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