Unraveling Genomic Diversity in Pseudomonas aeruginosa Cystic Fibrosis Lung Infection and Its Impact on Antimicrobial Resistance

• Type of Material: Article
• Authors: Jelly Vanderwoude, Georgia Institute of Technology, Atlanta; Sheyda Azimi, Georgia State University; Timothy D Read, Emory University; Stephen P Diggle, Georgia Institute of Technology, Atlanta
• Language: English
• Date: 2023-08-23
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
• License: Creative Commons Attribution-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1101/2023.06.14.544983
• Title of Journal or Parent Work: bioRxiv
• Grant/Funding Information: Georgia Institute of Technology, the Cystic Fibrosis Foundation for grants (DIGGLE18I0 and DIGGLE20G0) to S.P.D. and a fellowship to S.A. (AZIMI18F0), CF@LANTA for a fellowship to S.A. (3206AXB), the National Institutes of Health for a grant (R01AI153116) to S.P.D and T.R., and the National Science Foundation for a fellowship to J.V. (DGE-2039655).
• Keywords: hypermutation; evolution; population heterogeneity; antibiotic resistance
• Research Categories: Biology, General; Health Sciences, Medicine and Surgery

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen responsible for chronic, drug-resistant lung infections in individuals with cystic fibrosis (CF). Although extensive heterogeneity in antimicrobial resistance (AMR) phenotypes of P. aeruginosa CF lung populations has been previously described, there has yet to be a thorough investigation on how genomic diversification drives the evolution of AMR diversity within a population. In this study, we harnessed sequencing from a collection of 300 clinical isolates of P. aeruginosa to unravel the evolution of resistance diversity in four individuals with CF. We found that genomic diversity was not always a reliable predictor of phenotypic AMR diversity within a population, and notably, the least genetically diverse population in this cohort displayed AMR diversity comparable to that of populations with up to two orders of magnitude more SNPs. Hypermutator strains often displayed increased sensitivity to antimicrobials, even when there was a history of use of antimicrobial in the treatment of the patient. Lastly, we sought to determine whether diversity in AMR could be explained by evolutionary trade-offs with other traits. Our results showed no strong evidence of collateral sensitivity between aminoglycoside, beta-lactam, or fluoroquinolone antibiotics within these populations. Additionally, there was no evidence of trade-offs between AMR and growth in a sputum-mimicking environment. Overall, our findings highlight that (i) genomic diversity within a population is not a necessary precursor to phenotypic diversity in AMR; (ii) hypermutator populations can evolve increased sensitivity to antimicrobials even under apparent antibiotic selection; and that (iii) resistance to a single antibiotic may not impose enough of a fitness cost to elicit trade-offs with fitness.