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Targets for Combating the Evolution of Acquired Antibiotic Resistance.

Culyba MJ, Mo CY, Kohli RM - Biochemistry (2015)

Bottom Line: This recognition underscores the importance of understanding how such genetic changes can arise.We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets.We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal.

View Article: PubMed Central - PubMed

ABSTRACT
Bacteria possess a remarkable ability to rapidly adapt and evolve in response to antibiotics. Acquired antibiotic resistance can arise by multiple mechanisms but commonly involves altering the target site of the drug, enzymatically inactivating the drug, or preventing the drug from accessing its target. These mechanisms involve new genetic changes in the pathogen leading to heritable resistance. This recognition underscores the importance of understanding how such genetic changes can arise. Here, we review recent advances in our understanding of the processes that contribute to the evolution of antibiotic resistance, with a particular focus on hypermutation mediated by the SOS pathway and horizontal gene transfer. We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets. We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal.

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Cycles of drug discovery and antimicrobial resistance. An illustrativeschematic is shown presenting several generations of β-lactamantibiotics chronologically coupled to the β-lactamases thathave emerged in clinical pathogens to counteract these “next-generation”antibiotics.
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fig1: Cycles of drug discovery and antimicrobial resistance. An illustrativeschematic is shown presenting several generations of β-lactamantibiotics chronologically coupled to the β-lactamases thathave emerged in clinical pathogens to counteract these “next-generation”antibiotics.

Mentions: While innovative newapproaches are underway to discover antimicrobialswith different mechanisms of action,11−13 the most conventionalapproach to overcoming resistance has involved the chemical modificationof existing antibiotic scaffolds.14 Ourantibiotic arsenal has undergone a stepwise tailoring of core structures,akin to evolution, to both increase their spectrum of activity andovercome resistance mechanisms. For example, antibiotics that maintainthe β-lactam core started with penicillins, moved forward through“generations” of cephalosporins, and onward to carbapenems.While these “next-generation” antibiotics could overcomesome existing resistance mechanisms, many bacteria, in turn, haverapidly adapted to counteract these drugs (Figure 1).


Targets for Combating the Evolution of Acquired Antibiotic Resistance.

Culyba MJ, Mo CY, Kohli RM - Biochemistry (2015)

Cycles of drug discovery and antimicrobial resistance. An illustrativeschematic is shown presenting several generations of β-lactamantibiotics chronologically coupled to the β-lactamases thathave emerged in clinical pathogens to counteract these “next-generation”antibiotics.
© Copyright Policy - editor-choice
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4471857&req=5

fig1: Cycles of drug discovery and antimicrobial resistance. An illustrativeschematic is shown presenting several generations of β-lactamantibiotics chronologically coupled to the β-lactamases thathave emerged in clinical pathogens to counteract these “next-generation”antibiotics.
Mentions: While innovative newapproaches are underway to discover antimicrobialswith different mechanisms of action,11−13 the most conventionalapproach to overcoming resistance has involved the chemical modificationof existing antibiotic scaffolds.14 Ourantibiotic arsenal has undergone a stepwise tailoring of core structures,akin to evolution, to both increase their spectrum of activity andovercome resistance mechanisms. For example, antibiotics that maintainthe β-lactam core started with penicillins, moved forward through“generations” of cephalosporins, and onward to carbapenems.While these “next-generation” antibiotics could overcomesome existing resistance mechanisms, many bacteria, in turn, haverapidly adapted to counteract these drugs (Figure 1).

Bottom Line: This recognition underscores the importance of understanding how such genetic changes can arise.We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets.We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal.

View Article: PubMed Central - PubMed

ABSTRACT
Bacteria possess a remarkable ability to rapidly adapt and evolve in response to antibiotics. Acquired antibiotic resistance can arise by multiple mechanisms but commonly involves altering the target site of the drug, enzymatically inactivating the drug, or preventing the drug from accessing its target. These mechanisms involve new genetic changes in the pathogen leading to heritable resistance. This recognition underscores the importance of understanding how such genetic changes can arise. Here, we review recent advances in our understanding of the processes that contribute to the evolution of antibiotic resistance, with a particular focus on hypermutation mediated by the SOS pathway and horizontal gene transfer. We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets. We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal.

Show MeSH