Abstract
BackgroundThe emergence and spread of antibiotic resistance in bacteria is becoming a global public health problem. Combination therapy, i.e., the simultaneous use of multiple antibiotics, is used for long-term treatment to suppress the emergence of resistant strains. However, the effect of the combinatorial use of multiple drugs on the development of resistance remains elusive, especially in a quantitative assessment.ResultsTo understand the evolutionary dynamics under combination therapy, we performed laboratory evolution of Escherichia coli under simultaneous addition of two-drug combinations. We demonstrated that simultaneous addition of a certain combinations of two drugs with collateral sensitivity to each other could suppress the acquisition of resistance to both drugs. Furthermore, we found that the combinatorial use of enoxacin, a DNA replication inhibitor, with Chloramphenicol can accelerate acquisition of resistance to Chloramphenicol. Genome resequencing analyses of the evolved strains suggested that the acceleration of resistance acquisition was caused by an increase of mutation frequency when enoxacin was added.ConclusionsIntegration of laboratory evolution and whole-genome sequencing enabled us to characterize the development of resistance in bacteria under combination therapy. These results provide a basis for rational selection of antibiotic combinations that suppress resistance development effectively.
Highlights
The emergence and spread of antibiotic resistance in bacteria is becoming a global public health problem
The same study demonstrated that the resistant strains to these drugs exhibited collateral resistance/sensitivity to other drugs, which likely contribute to determining the course of antibiotic resistance evolution
We demonstrated that addition of ENX accelerated the development of CP resistance compared to the single use of CP
Summary
The emergence and spread of antibiotic resistance in bacteria is becoming a global public health problem. Combination therapy, i.e., the simultaneous use of multiple antibiotics, is used for long-term treatment to suppress the emergence of resistant strains. The emergence of antibiotic-resistant bacteria is a serious and worsening global public health problem, despite our efforts to suppress and to control it [1, 2]. Clinical uses of antibiotics have provided a selective advantage for naturally emerged resistant bacteria which renders antibiotics ineffective [3]. The use of multidrug combinations, both sequentially and simultaneously, is increasingly important to counteract the emergence of antibiotic resistant bacterial pathogens [8]. A better understanding of these phenomena is important since they could potentially inform about strategies to suppress the emergence of resistant strains by using multidrug
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