Acceleration and suppression of resistance development by antibiotic combinations

• Published in: BMC genomics Vol. 18; no. 1; p. 328
• Main Authors: Suzuki, Shingo, Horinouchi, Takaaki, Furusawa, Chikara
• Format: Journal Article
• Language: English
• Published: England BioMed Central 26.04.2017; BMC
• Subjects: Acceleration; Acquisitions & mergers; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Antibiotics; Bacteria; Chloramphenicol; Chloromycetin; Combinatorial analysis; Deoxyribonucleic acid; Directed Molecular Evolution; DNA; DNA biosynthesis; Drug development; Drug Interactions; Drug resistance; Drug Resistance, Bacterial - genetics; Drug Resistance, Multiple, Bacterial - genetics; E coli; Emergence; Enoxacin; Epistasis, Genetic; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - genetics; Evolution; Gene sequencing; Genomes; Genomics; Laboratories; Laboratory evolution; Metabolism; Mutation; Protein synthesis; Proteins; Public health; Strains (organisms); Studies; Therapy; Whole genome sequencing; Escherichia coli; Laboratory evolution; Antibiotic resistance
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-017-3718-2

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. However, the effect of the combinatorial use of multiple drugs on the development of resistance remains elusive, especially in a quantitative assessment. To 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. Integration 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.