Investigating the effects of genetic background on the fitness of quinolone resistant mutations in Escherichia coli
Antimicrobial resistance (AMR) has been revealed to be a major threat to public health. Invasive bacterial infections are the leading cause of child mortality and morbidity around the world . With the growing occurrence of AMR, controlling such bacterial infections has become more and more challenging. If action is not taken to manage the situation it is predicated that by 2050 AMR will result in 10 million deaths per year . AMR occurs when bacteria or other microbes resist the effects of an antibiotic, the microbe becomes immune and reduces or eliminates the effectiveness of drugs, chemicals, or other agents that are designed to cure or prevent infections . In general, resistance to antibiotics occurs by chromosomal mutations or horizontal gene transfer of resistance elements . The aim is to validate the putative synthetic lethal/sick interactions of quinolone resistance mutations in conditional knockout strain of E. coli.
Antimicrobial resistance (AMR) occurs when microbes become resistant to the antibiotics that are designed to cure them. Genetic interactions or epistasis of AMR mutations play an important role in determining the predictability and the persistence of AMR. Synthetic lethality is an example of genetic interactions, whereby when separated two mutations are viable but when combined are lethal. This validates the putative synthetic lethal/sick interactions of quinolone resistance mutations in 17 conditional knockout E. coli strains. The quinolone resistance mutations examined were gyrase A (gyrA) mutations, which include S83L, D87N or S83L-D87N combined. The results showed that 16/17 knockout strains showed reduced phenotypic fitness. Genes whose knockout alleles are synthetically lethal with one or more AMR mutation are potential candidates as drug targets. This study has demonstrated a new therapeutic method to combat AMR mutations by utilizing the concept of synthetic lethal interactions.