Synergistic action of 6-gingerol as an adjuvant to colistin for susceptibility enhancement in multidrug-resistant Klebsiella pneumoniae isolates
Ontology highlight
ABSTRACT:
SUBMITTER: Sahoo M
PROVIDER: S-EPMC10912974 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Sequence type 258 (ST258) is the most widespread multidrug resistant (MDR) Klebsiella pneumoniae strain worldwide. Here, we report the draft genome sequences of two colistin-resistant MDR K. pneumoniae ST258 clinical strains isolated from hospital patients in Italy. These strains are resistant to β-lactams, cephalosporins, fluoroquinolones, aminoglycosides, macrolides, tetracyclines, carbapenems, and colistin.
| S-EPMC3569348 | biostudies-literature
Project description:Multidrug resistant Enterobacterales have become a serious global health problem, with extended hospital stay and increased mortality. Antibiotic monotherapy has been reported ineffective against most drug resistant bacteria including Klebsiella pneumoniae, thus encouraging the use of multidrug therapies as an alternative antibacterial strategy. The present works assessed the antibacterial activity of colistin against K. pneumoniae isolates. Resistant isolates were tested against 16 conventional antibiotics alone and in combination with colistin. The results revealed that all colistin resistant isolates demonstrated multidrug resistance against the tested antibiotics except amikacin. At sub-inhibitory concentrations, combinations of colistin with amikacin, or fosfomycin showed synergism against 72.72% (8 of 11 isolates). Colistin with either of gentamicin, meropenem, cefoperazone, cefotaxime, ceftazidime, moxifloxacin, minocycline, or piperacillin exhibited synergism against 81.82% (9 of 11 isolates). Combinations of colistin with either of tobramycin or ciprofloxacin showed synergism against 45.45% (5 in 11 isolates), while combinations of colistin with imipenem or ceftolozane and tazobactam displayed 36.36% (4 of 11 isolates) and 63.64% (7 of 11 isolates) synergism. In addition, combinations of colistin with levofloxacin was synergistic against 90.91% (10 of 11 isolates). The results revealed that combinations of colistin with other antibiotics could effectively inhibit colistin resistant isolates of K. pneumoniae, and thus could be further explore for the treatment of multidrug resistant pathogens.
| S-EPMC7787437 | biostudies-literature
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.
| S-EPMC5993281 | biostudies-literature
Project description:ObjectivesPolymyxins (i.e., polymyxin B and colistin) are used as a last-line therapy to combat multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance in K. pneumoniae is increasingly reported worldwide. This study identified the genetic variations responsible for high-level colistin resistance in MDR K. pneumoniae clinical isolates.MethodsSixteen MDR K. pneumoniae isolates were obtained from stool samples of 8 patients before and after colistin treatment. Their genomes were sequenced on Illumina MiSeq to determine genetic variations.ResultsFifteen of 16 isolates harboured ISKpn26-like element insertion at nucleotide position 75 of mgrB, abolishing its negative regulation on phoPQ; while colistin-susceptible ATH7 contained intact mgrB and phoQ. Interestingly, each of the 7 mgrB-disrupted, colistin-susceptible isolates contained a nonsynonymous substitution in PhoQ (G39S, L239P, N253T or V446G), potentially impairing its function and intergenically suppressing the effect caused by mgrB inactivation. Additionally, three of the 7 corresponding mgrB-disrupted, colistin-resistant isolates harboured a secondary nonsynonymous substitution in PhoQ (N253P, D438H or T439P).ConclusionsThis is the first report of phoQ mutations in mgrB-disrupted, colistin-susceptible K. pneumoniae clinical isolates. We also discovered multiple phoQ mutations in mgrB-disrupted, colistin-resistant strains. Our findings highlight the multifaceted molecular mechanisms of colistin resistance in K. pneumoniae.
| S-EPMC7264071 | biostudies-literature
Project description:Carbapenem-resistant Enterobacteriaceae (CRE) is listed as an urgent threat by the World Health Organization because of the limited therapeutic options, rapid evolution of resistance mechanisms, and worldwide dissemination. Colistin is a common backbone agent among the "last-resort" antibiotics for CRE; however, its emerging resistance among CRE has taken the present dilemma to the next level. Azidothymidine (AZT), a thymidine analog used to treat human immunodeficiency virus/acquired immunodeficiency syndrome, has been known to possess antibacterial effects against Enterobacteriaceae. In this study, we investigated the combined effects of AZT and colistin in 40 clinical isolates of colistin-resistant, carbapenem-resistant K. pneumoniae (CCRKP). Eleven of the 40 isolates harbored Klebsiella pneumoniae carbapenemase. The in vitro checkerboard method and in vivo nematode killing assay both revealed synergistic activity between the two agents, with fractional inhibitory concentration indexes of ≤0.5 in every strain. Additionally, a significantly lower hazard ratio was observed for the nematodes treated with combination therapy (0.288; p < 0.0001) compared with either AZT or colistin treatment. Toxicity testing indicated potentially low toxicity of the combination therapy. Thus, the AZT-colistin combination could be a potentially favorable therapeutic option for treating CCRKP.
| S-EPMC7764370 | biostudies-literature
Project description:Colistin (polymyxin E) is increasingly used as a last-resort antibiotic for the treatment of severe infections with multidrug-resistant Gram-negative bacteria. In contrast to human medicine, colistin is also used in veterinary medicine for metaphylaxis. Our objective was to decipher common colistin resistance mechanisms in Klebsiella pneumoniae isolates from animals. In total, 276 veterinary K. pneumoniae isolates, derived from companion animals or livestock, and 12 isolates from human patients were included for comparison. Six out of 276 veterinary isolates were colistin resistant (2.2%). Human isolates belonging to high-risk clonal lineages (e.g., ST15, ST101, ST258), displayed multidrug-resistant phenotypes and harboured many resistance genes compared to the veterinary isolates. However, the common colistin resistance mechanism in both human and animal K. pneumoniae isolates were diverse alterations of MgrB, a critical regulator of lipid A modification. Additionally, deleterious variations of lipopolysaccharide (LPS)-associated proteins (e.g., PmrB P95L, PmrE P89L, LpxB A152T) were identified. Phylogenetic analysis and mutation patterns in genes encoding LPS-associated proteins indicated that colistin resistance mechanisms developed independently in human and animal isolates. Since only very few antibiotics remain to treat infections with MDR bacteria, it is important to further analyse resistance mechanisms and the dissemination within different isolates and sources.
| S-EPMC9686735 | biostudies-literature
Project description:Colistin is one of the last-resort therapeutic agents to combat multidrug-resistant Gram-negative bacteria (GNB) including Klebsiella pneumoniae. Although it happens rarely, resistance to colistin has been reported for several GNB. A total of 20 colistin resistant (col-R) and three colistin susceptible (col-S) clinical isolates of K. pneumoniae were studied to explore the underlying mechanisms of colistin resistance. The presence of plasmid encoded resistance genes, mcr-1, mcr-2, mcr-3, and mcr-4 genes were examined by PCR. The nucleotide sequences of pmrA, pmrB, phoP, phoQ, and mgrB genes were determined. To evaluate the association between colistin resistance and upregulation of pmrHFIJKLM and pmrCAB operons, transcriptional level of the pmrK and pmrC genes encoding for lipopolysaccharide target modifying enzymes was quantified by RT-qPCR analysis. None of the plasmid encoded resistance genes were detected in the studied isolates. Inactivation of MgrB due to nonsense mutations and insertion of IS elements was observed in 15 col-R isolates (75%). IS elements (IS5-like and IS1-like families) most commonly targeted the coding region and in one case the promoter region of the mgrB. Complementation with wild-type MgrB restored colistin susceptibility in isolates with altered mgrB. All col-R isolates lacked any genetic alterations in the pmrA, phoP, and phoQ genes and substitutions identified in the pmrB were not found to be involved in resistance conferring determined by complementation assay. Colistin resistance linked with upregulation of pmrHFIJKLM and pmrCAB operons with the pmrK and pmrC being overexpressed in 20 and 11 col-R isolates, respectively. Our results demonstrated that MgrB alterations are the major mechanisms contributing to colistin resistance in the tested K. pneumoniae isolates from Iran.
| S-EPMC5741654 | biostudies-literature
Project description:Multidrug-resistant Gram-negative bacteria are a rapidly growing public health threat, and the development of novel antimicrobials has failed to keep pace with their emergence. Synergistic combinations of individually ineffective drugs present a potential solution, yet little is understood about the mechanisms of most such combinations. Here, we show that the combination of colistin (polymyxin E) and minocycline has a high rate of synergy against colistin-resistant and minocycline-intermediate or -resistant strains of Klebsiella pneumoniae. Furthermore, using transcriptome sequencing (RNA-Seq), we characterized the transcriptional profiles of these strains when treated with the drugs individually and in combination. We found a striking similarity between the transcriptional profiles of bacteria treated with the combination of colistin and minocycline at individually subinhibitory concentrations and those of the same isolates treated with minocycline alone. We observed a similar pattern with the combination of polymyxin B nonapeptide (a polymyxin B analogue that lacks intrinsic antimicrobial activity) and minocycline. We also found that genes involved in polymyxin resistance and peptidoglycan biosynthesis showed significant differential gene expression in the different treatment conditions, suggesting possible mechanisms for the antibacterial activity observed in the combination. These findings suggest that the synergistic activity of this combination against bacteria resistant to each drug alone involves sublethal outer membrane disruption by colistin, which permits increased intracellular accumulation of minocycline.
| S-EPMC8923212 | biostudies-literature
Project description:BackgroundIncreasing use of colistin has led to the world-wide emergence of mobile colistin resistant gene (mcr). The present study aimed to identify and characterise mcr and other drug-resistant genes in colistin resistant Klebsiella pneumoniae clinical isolates.MethodsTwenty-two colistin resistant K. pneumoniae were analysed for mcr and other drug-resistant genes, efflux pumps, and virulence genes, and for their biofilm forming ability. Pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST) were performed for all mcr-1 positive isolates. S1-PFGE and Southern hybridisation were performed for localisation of mcr-1 and bla NDM.ResultsNineteen colistin resistant K. pneumoniae harboured mcr-1 and 3 had mgrB disruption. All isolates harboured bla OXA-48-type and ESBL genes; eight strains (five with mcr-1 and three with mgrB disruption) co-harboured bla NDM. Efflux pumps genes AcrAB and mdtK were detected in all 22 and tol-C in 21 isolates. Virulence-related genes entB and irp-1 were detected in all 22, mrkD in 20, and fimH-1 in 18 isolates; 11 isolates were strong biofilm producers. PFGE clustered mcr-1 positive isolates into eight groups based on ≥90% similarity; MLST revealed diverse sequence types, predominant being ST-15 (n = 4) and ST-16 (n = 4). Both mcr-1 and bla NDM were localised on plasmid and chromosome; mcr-1 was present on IncFII type and bla NDM on IncFIB and IncA/C type plasmids.ConclusionsColistin resistance in K. pneumoniae was predominantly mediated by mcr-1. Co-existence of colistin, carbapenem, and other drug-resistant genes along with efflux pumps indicates towards enormous genomic plasticity in K. pneumoniae with ability to emerge as super-spreader of drug-resistance.
| S-EPMC8256276 | biostudies-literature
Project description:Heteroresistance to colistin can be defined as the presence of resistant subpopulations in an isolate that is susceptible to this antibiotic. Colistin resistance in Gram-negative bacteria is more frequently related to chromosomal mutations and insertions. This work aimed to study heteroresistance in nine clinical isolates of Klebsiella pneumoniae producing OXA-48 and to describe genomic changes in mutants with acquired resistance in vitro. Antimicrobial susceptibility was determined by broth microdilution (BMD) and heteroresistance by population analysis profiling (PAP). The proteins related to colistin resistance were analyzed for the presence of mutations. Additionally, PCR of the mgrB gene was performed to identify the presence of insertions. In the nine parental isolates, the PAP method showed colistin heteroresistance of colonies growing on plates with concentrations of up to 64 mg/L, corresponding to stable mutant subpopulations. The MICs of some mutants from the PAP plate containing 4×MIC of colistin had absolute values of ≤2 mg/L that were higher than the parental MICs and were defined as persistent variants. PCR of the mgrB gene identified an insertion sequence that inactivated the gene in 21 mutants. Other substitutions in the investigated mutants were found in PhoP, PhoQ, PmrB, PmrC, CrrA and CrrB proteins. Colistin heteroresistance in K. pneumoniae isolates was attributed mainly to insertions in the mgrB gene and point mutations in colistin resistance proteins. The results of this study will improve understanding regarding the mechanisms of colistin resistance in mutants of K. pneumoniae producing OXA-48.
| S-EPMC10375995 | biostudies-literature