Dissemination in Portugal of CTX-M-15-, OXA-1-, and TEM-1-producing Enterobacteriaceae strains containing the aac(6')-Ib-cr gene, which encodes an aminoglycoside- and fluoroquinolone-modifying enzyme.
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ABSTRACT:
SUBMITTER: Machado E
PROVIDER: S-EPMC1563523 | biostudies-literature | 2006 Sep
REPOSITORIES: biostudies-literature
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Dissemination in Portugal of CTX-M-15-, OXA-1-, and TEM-1-producing Enterobacteriaceae strains containing the aac(6')-Ib-cr gene, which encodes an aminoglycoside- and fluoroquinolone-modifying enzyme.
Machado Elisabete E Coque Teresa M TM Cantón Rafael R Baquero Fernando F Sousa João Carlos JC Peixe Luísa L
Antimicrobial agents and chemotherapy 20060901 9
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Project description:Enzymatic modification of aminoglycoside antibiotics mediated by regioselective aminoglycoside N-acetyltransferases is the predominant cause of bacterial resistance to aminoglycosides. A recently discovered bifunctional aminoglycoside acetyltransferase (AAC(6')-Ib variant, AAC(6')-Ib-cr) has been shown to catalyze the acetylation of fluoroquinolones as well as aminoglycosides. We have expressed and purified AAC(6')-Ib-wt and its bifunctional variant AAC(6')-Ib-cr in Escherichia coli and characterized their kinetic and chemical mechanism. Initial velocity and dead-end inhibition studies support an ordered sequential mechanism for the enzyme(s). The three-dimensional structure of AAC(6')-Ib-wt was determined in various complexes with donor and acceptor ligands to resolutions greater than 2.2 A. Observation of the direct, and optimally positioned, interaction between the 6'-NH 2 and Asp115 suggests that Asp115 acts as a general base to accept a proton in the reaction. The structure of AAC(6')-Ib-wt permits the construction of a molecular model of the interactions of fluoroquinolones with the AAC(6')-Ib-cr variant. The model suggests that a major contribution to the fluoroquinolone acetylation activity comes from the Asp179Tyr mutation, where Tyr179 makes pi-stacking interactions with the quinolone ring facilitating quinolone binding. The model also suggests that fluoroquinolones and aminoglycosides have different binding modes. On the basis of kinetic properties, the pH dependence of the kinetic parameters, and structural information, we propose an acid/base-assisted reaction catalyzed by AAC(6')-Ib-wt and the AAC(6')-Ib-cr variant involving a ternary complex.
| S-EPMC2855648 | biostudies-literature
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| S-EPMC2612178 | biostudies-literature
Project description:Emergence of multidrug-resistant Salmonella typhimurium strains, especially the ACSSuT and nalidixic acid R types, has significantly compromised the effectiveness of current strategies to control Salmonella infections, resulting in increased morbidity and mortality. Clinical S. typhimurium isolates recovered in Hong Kong during the period of 2005-2011 were increasingly resistant to ciprofloxacin (CIP) and antibiotics of the ACSSuT group. Our data revealed that oqxAB and aac(6')Ib-cr were encoded on plasmids of various sizes and the presence of these two elements together with a single gyrA mutation in S. typhimurium were sufficient to mediate resistance to CIP. Acquisition of the oqxAB and aac(6')Ib-cr encoding plasmids by S. typhimurium caused a fourfold increase in CIP minimal inhibitory concentration. Furthermore, the presence of oqxAB and aac(6')Ib-cr in Salmonella dramatically increased the mutation prevention concentration of CIP which may due to mutational changes in the drug target genes. In conclusion, possession of oqxAB and aac(6')Ib-cr encoding plasmid facilitate the selection of CIP resistant S. typhimurium, thereby causing a remarkable increase of CIP resistance among clinical Salmonella strains in Hong Kong.
| S-EPMC4183184 | biostudies-literature
Project description:Enzymatic modification is a prevalent mechanism by which bacteria defeat the action of antibiotics. Aminoglycosides are often inactivated by aminoglycoside modifying enzymes encoded by genes present in the chromosome, plasmids, and other genetic elements. The AAC(6')-Ib (aminoglycoside 6'-N-acetyltransferase type Ib) is an enzyme of clinical importance found in a wide variety of gram-negative pathogens. The AAC(6')-Ib enzyme is of interest not only because of his ubiquity but also because of other characteristics, it presents significant microheterogeneity at the N-termini and the aac(6')-Ib gene is often present in integrons, transposons, plasmids, genomic islands, and other genetic structures. Excluding the highly heterogeneous N-termini, there are 45 non-identical AAC(6')-Ib related entries in the NCBI database, 32 of which have identical name in spite of not having identical amino acid sequence. While some variants conserved similar properties, others show dramatic differences in specificity, including the case of AAC(6')-Ib-cr that mediates acetylation of ciprofloxacin representing a rare case where a resistance enzyme acquires the ability to utilize an antibiotic of a different class as substrate. Efforts to utilize antisense technologies to turn off expression of the gene or to identify enzymatic inhibitors to induce phenotypic conversion to susceptibility are under way.
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Project description:Here, we report that the genetic structure of Tn1331 remained conserved in Argentina from 1989 to 2013 (72 of 73 isolates), with the exception being the plasmid-borne Tn1331-like transposon Tn6238 containing a new aac(6')-Ib-cr allele recovered from a colistin-resistant Klebsiella pneumoniae clinical isolate. A bioinformatic analysis of aac(6')-Ib-like gene cassettes suggests that this new aac(6')-Ib-cr allele emerged through mutation or homologous recombination in the Tn1331 genetic platform. Tn6238 is a novel platform for the dissemination of aminoglycoside and fluoroquinolone resistance determinants.
| S-EPMC4394824 | biostudies-literature
Project description:ObjectivesKPC-producing Klebsiella pneumoniae (KPC-Kp) isolates commonly co-harbour the aminoglycoside-modifying enzyme (AME) gene aac(6')-Ib, which encodes an AME that can confer resistance to some of the commercially available aminoglycosides. We sought to determine the influence of AAC(6')-Ib in KPC-Kp on the pharmacodynamic activity of aminoglycosides.MethodsSix KPC-Kp clinical isolates, three with and three without aac(6')-Ib, were analysed. Using these isolates, the bacterial killing of amikacin, gentamicin and tobramycin was assessed in static time-kill experiments. The pharmacodynamic activity of the aminoglycosides was then assessed in a dynamic one-compartment infection model over 72 h using simulated human pharmacokinetics of once-daily dosing with amikacin (15 mg/kg), gentamicin (5 mg/kg) and tobramycin (5 mg/kg).ResultsAt clinically relevant aminoglycoside concentrations in time-kill experiments and the dynamic one-compartment model, gentamicin was more active than amikacin or tobramycin against the isolates harbouring aac(6')-Ib. Amikacin, gentamicin and tobramycin all showed progressively reduced bacterial killing with exposure to repeated doses against most isolates in the dynamic one-compartment model. MIC values were generally not a good predictor of gentamicin pharmacodynamic activity against KPC-Kp, but were more reliable for amikacin and tobramycin.ConclusionsGentamicin may be preferred over amikacin or tobramycin for treatment of KPC-Kp infections. However, gentamicin MICs are not a consistent predictor of its pharmacodynamic activity and unexpected treatment failures are possible.
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Project description:AAC(6')-Ib is an important aminoglycoside resistance enzyme to target with enzymatic inhibitors. An in silico screening approach was used to identify potential inhibitors from the ChemBridge library. Several compounds were identified, of which two of them, 4-[(2-{[1-(3-methylphenyl)-4,6-dioxo-2-thioxotetrahydro-5(2H)-pyrimidinylidene]methyl}phenoxy)methyl]benzoic acid and 2-{5-[(4,6-dioxo-1,3-diphenyl-2-thioxotetrahydro-5(2H)-pyrimidinylidene)methyl]-2-furyl}benzoic acid, showed micromolar activity in inhibiting acetylation of kanamycin A. These compounds are predicted to bind the aminoglycoside binding site of AAC(6')-Ib and exhibited competitive inhibition against kanamycin A.
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Project description:Quinolone resistance is an emerging problem in China. To investigate the prevalence of the plasmid-mediated quinolone resistance genes qnr and aac(6')-Ib-cr, a total of 265 clinical isolates of Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, and Enterobacter cloacae with ciprofloxacin MICs of > or =0.25 microg/ml were screened at nine teaching hospitals in China. The qnrA, qnrB, qnrS, and aac(6')-Ib genes were detected by PCR. The aac(6')-Ib-cr gene was further identified by digestion with BtsCI and/or direct sequencing. The qnr gene was present in significantly smaller numbers of isolates with cefotaxime MICs of <2 microg/ml than isolates with higher MICs (> or =2.0 microg/ml) (20.6% and 42.1%, respectively; P < 0.05). aac(6')-Ib-cr was present in 17.0% of the isolates tested, and 7.9% of the isolates carried both the qnr and the aac(6')-Ib-cr genes. Among the isolates with cefotaxime MICs of > or =2.0 microg/ml, qnr and aac(6')-Ib-cr were present in 65.7% and 8.6% of E. cloacae isolates, respectively; 65.5% and 21.8% of K. pneumoniae isolates, respectively; 63.3% and 26.7% of C. freundii isolates, respectively; and 6.5% and 16.9% of E. coli isolates, respectively. The 20 transconjugants showed 16- to 128-fold increases in ciprofloxacin MICs, 14 showed 16- to 2,000-fold increases in cefotaxime MICs, and 5 showed 8- to 32-fold increases in cefoxitin MICs relative to those of the recipient due to the cotransmission of bla(CTX-M-14), bla(CTX-M-3), bla(DHA-1), bla(SHV-2), and bla(SHV-12) with the qnr and aac(6')-Ib-cr genes. Southern hybridization analysis showed that these genes were located on large plasmids of different sizes (53 to 193 kb). These findings indicate the high prevalence of qnr and aac(6')-Ib-cr in members of the family Enterobacteriaceae and the widespread dissemination of multidrug resistance in China.
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Project description:aac(6')-Ib-cr is a plasmid-mediated quinolone resistance gene embedded within a gene cassette, most often within an integron. It confers resistance to quinolones and aminoglycosides. We investigated the role of a 101-bp fragment frequently present upstream of the aac(6')-Ib-cr gene cassette and found that it contributes to the expression of aac(6')-Ib-cr and provides an alternative start codon, confirming the length of the AAC(6')-Ib-cr protein to 199 amino acids.
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Project description:We investigated the prevalence of plasmid-mediated quinolone resistance (PMQR) genes in avian pathogenic Escherichia coli (APEC) strains in Japan. A total of 117 APEC strains collected between 2004 and 2007 were examined for PMQR genes (qnrA, qnrB, qnrC, qnrD, qnrS, aac(6')-Ib-cr, qepA and oqxAB) by polymerase chain reaction. None of the APEC strains carried qnrA, qnrB, qnrC, qnrD, qnrS, qepA or oqxAB, but one of the isolates was identified as an AAC (6')-Ib-cr producer. Phylogenetic grouping, multi-locus sequence typing and serotyping showed that this isolate belonged to phylogenetic group A, sequence type 167 and untypable serogroup. To our knowledge, this is the first report of the aac (6')-Ib-cr gene in bacteria from food-producing animals in Japan.
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