AI Article Synopsis
- A fluoroquinophenoxazine compound (FP-11g) shows effective inhibition of bacterial topoisomerase I and displays strong antituberculosis activity with a minimal inhibitory concentration (MIC) of 2.5 μM against Mycobacterium tuberculosis.
- The compound exhibited bactericidal properties against Mycobacterium smegmatis, resulting in significant reductions in viable bacterial counts after incubation and also demonstrated some efficacy against Mycobacterium abscessus.
- Resistance mechanisms were studied by isolating mutants of M. smegmatis through whole-genome sequencing, revealing mutations that may influence the compound's uptake, while highlighting that FP-11g's interactions with DNA are essential but not solely responsible for its antimicrobial effects
Article Abstract
We have previously reported the inhibition of bacterial topoisomerase I activity by a fluoroquinophenoxazine compound (FP-11g) with a 6-bipiperidinyl lipophilic side chain that exhibited promising antituberculosis activity (MIC = 2.5 μM against Mycobacterium tuberculosis, SI = 9.8). Here, we found that the compound is bactericidal towards Mycobacterium smegmatis, resulting in greater than 5 Log10 reduction in colony-forming units [cfu]/mL following a 10 h incubation at 1.25 μM (4X MIC) concentration. Growth inhibition (MIC = 50 μM) and reduction in cfu could also be observed against a clinical isolate of Mycobacterium abscessus. Stepwise isolation of resistant mutants of M. smegmatis was conducted to explore the mechanism of resistance. Mutations in the resistant isolates were identified by direct comparison of whole-genome sequencing data from mutant and wild-type isolates. These include mutations in genes likely to affect the entry and retention of the compound. FP-11g inhibits Mtb topoisomerase I and Mtb gyrase with IC50 of 0.24 and 27 μM, respectively. Biophysical analysis showed that FP-11g binds DNA as an intercalator but the IC50 for inhibition of Mtb topoisomerase I activity is >10 fold lower than the compound concentrations required for producing negatively supercoiled DNA during ligation of nicked circular DNA. Thus, the DNA-binding property of FP-11g may contribute to its antimycobacterial mechanism, but that alone cannot account for the observed inhibition of Mtb topoisomerase I.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386362 | PMC |
| http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207733 | PLOS |
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