Exploring Antimicrobial Combination Efficacy Network through Profiling Collateral Sensitivity, Cross-Resistance and Tolerance Trade-Offs during Evolution of Antibiotic Resistance in Acinetobacter baumannii
Antimicrobial resistance (AMR) is currently estimated for over 700,000 deaths annually and with its exponential progression is projected to reach at a level of above 10 million deaths per year by 2050. For infections caused by Gram-negative bacteria (such as Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter) we are virtually exhausted all treatment options. However, the pipeline for antibiotics and other antimicrobial is drought with five drugs have been marketed in the present century so far. The emergence of antibiotic resistance is essentially a consequence of evolutionary processes. Hence the quest of a viable and sustainable strategy should consider evolutionary dynamics and trade-offs. Under pinning cross-resistance and collateral sensitivity to laboratory raised or clinical resistant isolates and the mechanism for such trade-offs have already providing crucial clue is developing combinatorial or drug cycling therapeutics. Predicting antimicrobial efficacy network (ACE) via robust statistical pipeline and experimental validation under single or multidrug exposure to evaluate potential for evolved collateral sensitivities between drug/ drug-combinations accounted for a reduction in bacterial adaptability and likelihood for population extinction. Such approach have been adopted against Escherichia coli and P. auroginosa offering opportunities to improve sustainability of antibiotic therapy curbing resistance evolution. The present proposal aims evolution of A. baumannii resistance is considering carbapenem and colistin resistance as models for systemic CR-CS network identification, adaptability and extinction break points and mechanistic exploration of evolutionary trade-offs. Alongside, drug tolerance associated attributes throughout evolution of resistance would be introspected for possible persistence accompanying resistance emergence.