Hijacking a small plasmid to confer high-level resistance to aztreonam-avibactam and ceftazidime-avibactam. 2023

Ke Ma, and Yu Feng, and Alan McNally, and Zhiyong Zong
Centre of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Chengdu, China; Department of Infectious Diseases, The Affiliated Hospital, Guizhou Medical University, Guiyang, China.

Acquired β-lactamase-encoding genes are typically carried by large plasmids in Gram-negative bacteria, which also commonly carry multi-copy small plasmids. This study found that mobile genetic elements carrying antimicrobial resistance genes are capable of hijacking small plasmids. This study focused on aztreonam-avibactam (ATM-AVI) as this combination can be used to effectively counter almost all β-lactamases produced by bacteria, and has been recommended against carbapenem-resistant Enterobacterales. A clinical strain (085003) of carbapenem-resistant Escherichia coli was investigated, and mutants (085003R32 and 085003R512) able to grow under 32/4 and 512/4 mg/L of ATM-AVI were obtained as representatives of low- and high-level resistance, respectively, by induction. Comparative genomics showed that 085003R32 and 085003R512 had a single nucleotide mutation of β-lactamase gene blaCMY-2, encoding a novel CMY with a Thr319Ile substitution, assigned 'CMY-2R'. Cloning and enzyme kinetics were used to verify that CMY-2R conferred ATM-AVI resistance by compromising binding of AVI and subsequent protection of ATM. Mechanisms for the discrepant resistance between 085003R32 and 085003R512 were investigated. Three tandem copies of blaCMY-2R were identified on a self-transmissible IncP1 plasmid of 085003R32 due to IS1294 misrecognizing its end terIS and rolling-circle replication. 085003R512 had only a single copy of blaCMY-2R on the IncP1 plasmid, but possessed anther blaCMY-2R on an already present 4-kb small plasmid. IS1294-mediated mobilization on to this multi-copy small plasmid increased the copy number of blaCMY-2R significantly, rendering higher resistance. This study shows that bacteria can employ multiple approaches to accommodate selection pressures imposed by exposure to varied concentrations of antimicrobial agents.

UI MeSH Term Description Entries
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D010957 Plasmids Extrachromosomal, usually CIRCULAR DNA molecules that are self-replicating and transferable from one organism to another. They are found in a variety of bacterial, archaeal, fungal, algal, and plant species. They are used in GENETIC ENGINEERING as CLONING VECTORS. Episomes,Episome,Plasmid
D002442 Ceftazidime Semisynthetic, broad-spectrum antibacterial derived from CEPHALORIDINE and used especially for Pseudomonas and other gram-negative infections in debilitated patients. Ceftazidime Anhydrous,Ceftazidime Pentahydrate,Fortaz,Fortum,GR-20263,LY-139381,Pyridinium, 1-((7-(((2-amino-4-thiazolyl)((1-carboxy-1-methylethoxy)imino)acetyl)amino)-2-carboxy-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-en-3-yl)methyl)-, inner salt, pentahydrate, (6R-(6alpha,7beta(Z)))-,Tazidime,GR 20263,GR20263,LY 139381,LY139381
D004338 Drug Combinations Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture. Drug Combination,Combination, Drug,Combinations, Drug
D004926 Escherichia coli A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc. Alkalescens-Dispar Group,Bacillus coli,Bacterium coli,Bacterium coli commune,Diffusely Adherent Escherichia coli,E coli,EAggEC,Enteroaggregative Escherichia coli,Enterococcus coli,Diffusely Adherent E. coli,Enteroaggregative E. coli,Enteroinvasive E. coli,Enteroinvasive Escherichia coli
D000900 Anti-Bacterial Agents Substances that inhibit the growth or reproduction of BACTERIA. Anti-Bacterial Agent,Anti-Bacterial Compound,Anti-Mycobacterial Agent,Antibacterial Agent,Antibiotics,Antimycobacterial Agent,Bacteriocidal Agent,Bacteriocide,Anti-Bacterial Compounds,Anti-Mycobacterial Agents,Antibacterial Agents,Antibiotic,Antimycobacterial Agents,Bacteriocidal Agents,Bacteriocides,Agent, Anti-Bacterial,Agent, Anti-Mycobacterial,Agent, Antibacterial,Agent, Antimycobacterial,Agent, Bacteriocidal,Agents, Anti-Bacterial,Agents, Anti-Mycobacterial,Agents, Antibacterial,Agents, Antimycobacterial,Agents, Bacteriocidal,Anti Bacterial Agent,Anti Bacterial Agents,Anti Bacterial Compound,Anti Bacterial Compounds,Anti Mycobacterial Agent,Anti Mycobacterial Agents,Compound, Anti-Bacterial,Compounds, Anti-Bacterial
D001398 Aztreonam A monocyclic beta-lactam antibiotic originally isolated from Chromobacterium violaceum. It is resistant to beta-lactamases and is used in gram-negative infections, especially of the meninges, bladder, and kidneys. It may cause a superinfection with gram-positive organisms. Az-threonam,Azactam,Azthreonam,SQ-26,776,Urobactam,Az threonam,SQ 26,776,SQ26,776
D001618 beta-Lactamases Enzymes found in many bacteria which catalyze the hydrolysis of the amide bond in the beta-lactam ring. Well known antibiotics destroyed by these enzymes are penicillins and cephalosporins. beta-Lactamase,beta Lactamase,beta Lactamases
D015780 Carbapenems A group of beta-lactam antibiotics in which the sulfur atom in the thiazolidine ring of the penicillin molecule is replaced by a carbon atom. THIENAMYCINS are a subgroup of carbapenems which have a sulfur atom as the first constituent of the side chain. Antibiotics, Carbapenem,Carbapenem,Carbapenem Antibiotics
D053961 Azabicyclo Compounds Bicyclic bridged compounds that contain a nitrogen which has three bonds. The nomenclature indicates the number of atoms in each path around the rings, such as [2.2.2] for three equal length paths. Some members are TROPANES and BETA LACTAMS. Azabicyclo(1.1.0)Butanes,Azabicyclo(2.2.2)Octanes,Azabicyclo(3.3.1)Nonanes,Azabicyclo(4.3.0)Nonanes,Azabicyclo(5.2.2)Undecanes

Related Publications

Ke Ma, and Yu Feng, and Alan McNally, and Zhiyong Zong
January 2024, International journal of antimicrobial agents,
Ke Ma, and Yu Feng, and Alan McNally, and Zhiyong Zong
August 2022, Microbial drug resistance (Larchmont, N.Y.),
Ke Ma, and Yu Feng, and Alan McNally, and Zhiyong Zong
January 1988, Reviews of infectious diseases,
Ke Ma, and Yu Feng, and Alan McNally, and Zhiyong Zong
February 2023, bioRxiv : the preprint server for biology,
Ke Ma, and Yu Feng, and Alan McNally, and Zhiyong Zong
October 2023, The Journal of antimicrobial chemotherapy,
Ke Ma, and Yu Feng, and Alan McNally, and Zhiyong Zong
September 2020, Journal of global antimicrobial resistance,
Ke Ma, and Yu Feng, and Alan McNally, and Zhiyong Zong
April 1992, FEMS microbiology letters,
Ke Ma, and Yu Feng, and Alan McNally, and Zhiyong Zong
February 2023, Microbiology spectrum,
Ke Ma, and Yu Feng, and Alan McNally, and Zhiyong Zong
March 2024, International journal of antimicrobial agents,
Ke Ma, and Yu Feng, and Alan McNally, and Zhiyong Zong
April 2017, Antimicrobial agents and chemotherapy,
Copied contents to your clipboard!