Dataset Information

6-Bromoindirubin-3'-oxime derivatives are highly active colistin adjuvants against Klebsiella pneumoniae.

ABSTRACT: Multidrug resistant (MDR) bacterial infections have become increasingly common, leading clinicians to rely on last-resort antibiotics such as colistin. However, the utility of colistin is becoming increasingly compromised as a result of increasing polymyxin resistance. Recently we discovered that derivatives of the eukaryotic kinase inhibitor meridianin D abrogate colistin resistance in several Gram-negative species. A subsequent screen of three commercial kinase inhibitor libraries led to the identification of several scaffolds that potentiate colistin activity, including 6-bromoindirubin-3'-oxime, which potently suppresses colistin resistance in Klebsiella pneumoniae. Herein we report the activity of a library of 6-bromoindirubin-3'-oxime analogs and identify four derivatives that show equal or increased colistin potentiation activity compared to the parent compound.

SUBMITTER: Li H

PROVIDER: S-EPMC9945867 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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6-Bromoindirubin-3'-oxime derivatives are highly active colistin adjuvants against <i>Klebsiella pneumoniae</i>.

Li Haoting H Mattingly Anne E AE Smith Richard D RD Melander Roberta J RJ Ernst Robert K RK Melander Christian C

RSC medicinal chemistry 20221201 2

Multidrug resistant (MDR) bacterial infections have become increasingly common, leading clinicians to rely on last-resort antibiotics such as colistin. However, the utility of colistin is becoming increasingly compromised as a result of increasing polymyxin resistance. Recently we discovered that derivatives of the eukaryotic kinase inhibitor meridianin D abrogate colistin resistance in several Gram-negative species. A subsequent screen of three commercial kinase inhibitor libraries led to the i ...[more]

PMID: 36846374

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Project description:Klebsiella pneumoniae, a pathogen of critical clinical concern, urgently demands effective therapeutic options owing to its drug resistance. Polymyxins are increasingly regarded as a last-line therapeutic option for the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections. However, polymyxin resistance in K. pneumoniae is an emerging issue. Here, we report that gallium nitrate (GaNt), an antimicrobial candidate, exhibits a potentiating effect on colistin against MDR K. pneumoniae clinical isolates. To further confirm this, we investigated the efficacy of combined GaNt and colistin in vitro using spot dilution and rapid time-kill assays and growth curve inhibition tests and in vivo using a murine lung infection model. The results showed that GaNt significantly increased the antimicrobial activity of colistin, especially in the iron-limiting media. Mechanistic studies demonstrated that bacterial antioxidant activity was repressed by GaNt, as revealed by RNA sequencing (RNA-seq), leading to intracellular accumulation of reactive oxygen species (ROS) in K. pneumoniae, which was enhanced in the presence of colistin. Therefore, oxidative stress induced by GaNt and colistin augments the colistin-mediated killing of wild-type cells, which can be abolished by dimethyl sulfoxide (DMSO), an effective ROS scavenger. Collectively, our study indicates that GaNt has a notable impact on the antimicrobial activity of colistin against K. pneumoniae, revealing the potential of GaNt as a novel colistin adjuvant to improve the treatment outcomes of bacterial infections. IMPORTANCE This study aimed to determine the antimicrobial activity of GaNt combined with colistin against Klebsiella pneumoniae in vitro and in vivo. Our results suggest that by combining GaNt with colistin, antioxidant activity was suppressed and reactive oxygen species accumulation was induced in bacterial cells, enhancing antimicrobial activity against K. pneumoniae. We found that GaNt functioned as an antibiotic adjuvant when combined with colistin by inhibiting the growth of multidrug-resistant K. pneumoniae. Our study provides insight into the use of an adjuvant to boost the antibiotic potential of colistin for treating infections caused by multidrug-resistant K. pneumoniae.

Project description:The emergence and dissemination of carbapenemases, bacterial enzymes able to inactivate most β-lactam antibiotics, in Enterobacteriaceae is of increasing concern. The concurrent spread of resistance against colistin, an antibiotic of last resort, further compounds this challenge further. Whole-genome sequencing (WGS) can play a significant role in the rapid and accurate detection/characterization of existing and emergent resistance determinants, an essential aspect of public health surveillance and response activities to combat the spread of antimicrobial resistant bacteria. In the current study, WGS data was used to characterize the genomic content of antimicrobial resistance genes, including those encoding carbapenemases, in 10 multidrug-resistant Klebsiella pneumoniae isolates from Pakistan. These clinical isolates represented five sequence types: ST11 (n = 3 isolates), ST14 (n = 3), ST15 (n = 1), ST101 (n = 2), and ST307 (n = 1). Resistance profiles against 25 clinically-relevant antimicrobials were determined by broth microdilution; resistant phenotypes were observed for at least 15 of the 25 antibiotics tested in all isolates except one. Specifically, 8/10 isolates were carbapenem-resistant and 7/10 isolates were colistin-resistant. The blaNDM-1 and blaOXA-48 carbapenemase genes were present in 7/10 and 5/10 isolates, respectively; including 2 isolates carrying both genes. No plasmid-mediated determinants for colistin resistance (e.g. mcr) were detected, but disruptions and mutations in chromosomal loci (i.e. mgrB and pmrB) previously reported to confer colistin resistance were observed. A blaOXA-48-carrying IncL/M-type plasmid was found in all blaOXA-48-positive isolates. The application of WGS to molecular epidemiology and surveillance studies, as exemplified here, will provide both a more complete understanding of the global distribution of MDR isolates and a robust surveillance tool useful for detecting emerging threats to public health.

Dataset Information

6-Bromoindirubin-3'-oxime derivatives are highly active colistin adjuvants against Klebsiella pneumoniae.

Publications

6-Bromoindirubin-3'-oxime derivatives are highly active colistin adjuvants against <i>Klebsiella pneumoniae</i>.

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