Evolutionary Trajectories toward High-Level β-Lactam/β-Lactamase Inhibitor Resistance in the Presence of Multiple β-Lactamases

Rajer, Fredrika; Allander, Lisa; Karlsson, Philip A.; Sandegren, Linus

doi:10.1128/aac.00290-22

Cited by 11 publications

(6 citation statements)

References 54 publications

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“…Furthermore, in an in vitro mutant selection study using a model E . coli system and recombinant plasmid, it has recently been reported that bla OXA-1 copy number amplification was associated with evolution towards piperacillin/tazobactam resistance in the laboratory, and was driven by IS 26 [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

Dulyayangkul,

Beavis,

Lee

et al. 2024

PLoS Pathog

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Amikacin and piperacillin/tazobactam are frequent antibiotic choices to treat bloodstream infection, which is commonly fatal and most often caused by bacteria from the family Enterobacterales. Here we show that two gene cassettes located side-by-side in and ancestral integron similar to In37 have been “harvested” by insertion sequence IS26 as a transposon that is widely disseminated among the Enterobacterales. This transposon encodes the enzymes AAC(6’)-Ib-cr and OXA-1, reported, respectively, as amikacin and piperacillin/tazobactam resistance mechanisms. However, by studying bloodstream infection isolates from 769 patients from three hospitals serving a population of 1.2 million people in South West England, we show that increased enzyme production due to mutation in an IS26/In37-derived hybrid promoter or, more commonly, increased transposon copy number is required to simultaneously remove these two key therapeutic options; in many cases leaving only the last-resort antibiotic, meropenem. These findings may help improve the accuracy of predicting piperacillin/tazobactam treatment failure, allowing stratification of patients to receive meropenem or piperacillin/tazobactam, which may improve outcome and slow the emergence of meropenem resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

Dulyayangkul,

Beavis,

Lee

et al. 2024

PLoS Pathog

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show abstract

“…The copy number of the resultant composite transposon can be amplified by IS26, increasing TEM-1 production and the MICs of various aminopenicillin/β-lactamase inhibitor combinations, including piperacillin/tazobactam (23)(24)(25). Furthermore, in an in vitro mutant selection study using a model E. coli system and recombinant plasmid, it has recently been reported that bla OXA-1 copy number amplification was associated with evolution towards piperacillin/tazobactam resistance in the laboratory, and was driven by IS26 (29).…”

Section: Discussionmentioning

confidence: 99%

Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

Dulyayangkul,

Beavis,

Lee

et al. 2023

Preprint

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Amikacin and piperacillin/tazobactam are frequent antibiotic choices to treat bloodstream infection, which is commonly fatal and most often caused by bacteria from the familyEnterobacterales. Here we show that two gene cassettes located side-by-side in and ancestral integron similar to In37have been “harvested” by insertion sequence IS26as a transposon that is already globally disseminated among theEnterobacterales. This transposon encodes the enzymes AAC(6’)-Ib-cr and OXA-1, reported, respectively, as amikacin and piperacillin/tazobactam resistance mechanisms. However, by studying bloodstream infection isolates from 769 patients from, three hospitals serving a population of 1.5 million people in South West England, we show that increased enzyme production due to mutation in an IS26/In37-derived hybrid promoter or, more commonly, transposon copy number amplification is required to simultaneously remove these two key therapeutic options; in many cases leaving only the last-resort antibiotic, meropenem. These findings may help improve the accuracy of predicting piperacillin/tazobactam treatment failure, allowing stratification of patients to receive meropenem or piperacillin/tazobactam, which may improve outcome and slow the emergence of meropenem resistance.

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“…Gene amplification -IS26-mediated amplification of beta-lactamase genes can foster resistance towards beta-lactams, including the newest combinations with beta-lactamase inhibitors [241].…”

Section: Consequence Examplementioning

confidence: 99%

Non-Canonical Aspects of Antibiotics and Antibiotic Resistance

Amábile-Cuevas,

Lund-Zaina

2024

Antibiotics

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The understanding of antibiotic resistance, one of the major health threats of our time, is mostly based on dated and incomplete notions, especially in clinical contexts. The “canonical” mechanisms of action and pharmacodynamics of antibiotics, as well as the methods used to assess their activity upon bacteria, have not changed in decades; the same applies to the definition, acquisition, selective pressures, and drivers of resistance. As a consequence, the strategies to improve antibiotic usage and overcome resistance have ultimately failed. This review gathers most of the “non-canonical” notions on antibiotics and resistance: from the alternative mechanisms of action of antibiotics and the limitations of susceptibility testing to the wide variety of selective pressures, lateral gene transfer mechanisms, ubiquity, and societal factors maintaining resistance. Only by having a “big picture” view of the problem can adequate strategies to harness resistance be devised. These strategies must be global, addressing the many aspects that drive the increasing prevalence of resistant bacteria aside from the clinical use of antibiotics.

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Evolutionary Trajectories toward High-Level β-Lactam/β-Lactamase Inhibitor Resistance in the Presence of Multiple β-Lactamases

Abstract: β-Lactam antibiotics are the first choice for the treatment of most bacterial infections. However, the increased prevalence of β-lactamases, in particular extended-spectrum β-lactamases, in pathogenic bacteria has severely limited the possibility of using β-lactam treatments.

Cited by 11 publications

References 54 publications

Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

Non-Canonical Aspects of Antibiotics and Antibiotic Resistance

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