Genome-wide analysis captures the determinants of the antibiotic cross-resistance interaction network

Abstract

Understanding how evolution of antimicrobial resistance increases resistance to other drugs is a challenge of profound importance. By combining experimental evolution and genome sequencing of 63 laboratory-evolved lines, we charted a map of cross-resistance interactions between antibiotics in Escherichia coli, and explored the driving evolutionary principles. Here, we show that (1) convergent molecular evolution is prevalent across antibiotic treatments, (2) resistance conferring mutations simultaneously enhance sensitivity to many other drugs and (3) 27% of the accumulated mutations generate proteins with compromised activities, suggesting that antibiotic adaptation can partly be achieved without gain of novel function. By using knowledge on antibiotic properties, we examined the determinants of cross-resistance and identified chemogenomic profile similarity between antibiotics as the strongest predictor. In contrast, cross-resistance between two antibiotics is independent of whether they show synergistic effects in combination. These results have important implications on the development of novel antimicrobial strategies.

Biophysical principles predict fitness landscapes of drug resistance

“…Experimental evolution studies of evolution of antibiotic resistance showed that in many cases resistance-conferring mutations arose both in target and off-pathway genes (5,11). However, mutations conferring resistance against trimethoprim (TMP) were largely limited to the target gene, namely the ORF and upstream region of folA, the gene encoding dihydrofolate reductase (DHFR) (1,5,11).…”

“…However, mutations conferring resistance against trimethoprim (TMP) were largely limited to the target gene, namely the ORF and upstream region of folA, the gene encoding dihydrofolate reductase (DHFR) (1,5,11). DHFR is an essential core metabolic enzyme that converts dihydrofolate to tetrahydrofolate-a main source of carbon atoms in several key pathways.…”

Negatively charged silver nanoparticles with potent antibacterial activity and reduced toxicity for pharmaceutical preparations

“…Indeed, most pathogenic bacteria become resistant with time to the action of antibiotics. 2,3 This effect represents a paramount medical problem so that new molecules and compounds with high and persistent antibacterial activity are required to face the challenge of emerging infections and the global spread of drug-resistant microbial pathogens. 4 In addition to the treatment of infections, novel preservatives are essential in pharmaceutical and cosmetic areas as an alternative solution to the widely used esters of p-hydroxybenzoic acid (parabens).…”

Effects of Stress, Reactive Oxygen Species, and the SOS Response on De Novo Acquisition of Antibiotic Resistance in Escherichia coli

“…The acquisition of antibiotic resistance under optimized culture conditions and the underlying molecular mechanisms causing the cellular response are well documented (2,(10)(11)(12). The second aim of this study was to investigate whether additional stress factors, such as low pH or increased NaCl concentrations, influence the ability of the cell to acquire antibiotic resistance de novo.…”