Mixed Strain Pathogen Populations Accelerate the Evolution of Antibiotic Resistance in Patients

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Jul 12

PMID 37438338

Authors

Julio Diaz Caballero

Rachel M Wheatley

Natalia Kapel

Carla Lopez-Causape

Thomas Van der Schalk

Angus Quinn

Liam P Shaw

Lois Ogunlana

Claudia Recanatini

Basil Britto Xavier

Leen Timbermont

Jan Kluytmans

Alexey Ruzin

Mark Esser

Surbhi Malhotra-Kumar

Antonio Oliver

R Craig MacLean

Affiliations

Soon will be listed here.

Abstract

Antibiotic resistance poses a global health threat, but the within-host drivers of resistance remain poorly understood. Pathogen populations are often assumed to be clonal within hosts, and resistance is thought to emerge due to selection for de novo variants. Here we show that mixed strain populations are common in the opportunistic pathogen P. aeruginosa. Crucially, resistance evolves rapidly in patients colonized by multiple strains through selection for pre-existing resistant strains. In contrast, resistance evolves sporadically in patients colonized by single strains due to selection for novel resistance mutations. However, strong trade-offs between resistance and growth rate occur in mixed strain populations, suggesting that within-host diversity can also drive the loss of resistance in the absence of antibiotic treatment. In summary, we show that the within-host diversity of pathogen populations plays a key role in shaping the emergence of resistance in response to treatment.

Citing Articles

Genomic resistance in historical clinical isolates increased in frequency and mobility after the age of antibiotics.

Kaul A, Souque C, Holland M, Baym M bioRxiv. 2025; .

PMID: 39868160 PMC: 11761691. DOI: 10.1101/2025.01.16.633422.

Drug combinations targeting antibiotic resistance.

Bognar B, Spohn R, Lazar V NPJ Antimicrob Resist. 2025; 2(1):29.

PMID: 39843924 PMC: 11721080. DOI: 10.1038/s44259-024-00047-2.

Efficacy of Ceftazidime-avibactam in treating Gram-negative infections: a systematic review and meta-analysis.

Khoshdel N, Noursalehigarakani M, Seghatoleslami Z, Hadavand F, Eghbal E, Nasiri M Eur J Clin Microbiol Infect Dis. 2025; .

PMID: 39841366 DOI: 10.1007/s10096-025-05044-5.

Integrative genomics would strengthen AMR understanding through ONE health approach.

Liu C, Pandey R Heliyon. 2025; 10(14):e34719.

PMID: 39816336 PMC: 11734142. DOI: 10.1016/j.heliyon.2024.e34719.

Evolution takes multiple paths to evolvability when facing environmental change.

Kumawat B, Lalejini A, Acosta M, Zaman L Proc Natl Acad Sci U S A. 2024; 122(1):e2413930121.

PMID: 39739809 PMC: 11725885. DOI: 10.1073/pnas.2413930121.

References

Barrett R, Schluter D . Adaptation from standing genetic variation. Trends Ecol Evol. 2007; 23(1):38-44. DOI: 10.1016/j.tree.2007.09.008. View

Juan C, Pena C, Oliver A . Host and Pathogen Biomarkers for Severe Pseudomonas aeruginosa Infections. J Infect Dis. 2017; 215(suppl_1):S44-S51. DOI: 10.1093/infdis/jiw299. View

Williams D, Fothergill J, Evans B, Caples J, Haldenby S, Walshaw M . Transmission and lineage displacement drive rapid population genomic flux in cystic fibrosis airway infections of a Pseudomonas aeruginosa epidemic strain. Microb Genom. 2018; 4(3). PMC: 5885019. DOI: 10.1099/mgen.0.000167. View

Chung H, Merakou C, Schaefers M, Flett K, Martini S, Lu R . Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections. Nat Commun. 2022; 13(1):1231. PMC: 8907320. DOI: 10.1038/s41467-022-28188-w. View

Gabrielaite M, Johansen H, Molin S, Nielsen F, Marvig R . Gene Loss and Acquisition in Lineages of Pseudomonas aeruginosa Evolving in Cystic Fibrosis Patient Airways. mBio. 2020; 11(5). PMC: 7593970. DOI: 10.1128/mBio.02359-20. View

San Millan A, Pena-Miller R, Toll-Riera M, Halbert Z, McLean A, Cooper B . Positive selection and compensatory adaptation interact to stabilize non-transmissible plasmids. Nat Commun. 2014; 5:5208. PMC: 4208098. DOI: 10.1038/ncomms6208. View

Kalil A, Metersky M, Klompas M, Muscedere J, Sweeney D, Palmer L . Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016; 63(5):e61-e111. PMC: 4981759. DOI: 10.1093/cid/ciw353. View

Juan C, Gutierrez O, Oliver A, Ayestaran J, Borrell N, Perez J . Contribution of clonal dissemination and selection of mutants during therapy to Pseudomonas aeruginosa antimicrobial resistance in an intensive care unit setting. Clin Microbiol Infect. 2005; 11(11):887-92. DOI: 10.1111/j.1469-0691.2005.01251.x. View

Aloush V, Navon-Venezia S, Seigman-Igra Y, Cabili S, Carmeli Y . Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact. Antimicrob Agents Chemother. 2005; 50(1):43-8. PMC: 1346794. DOI: 10.1128/AAC.50.1.43-48.2006. View

10.

Andersson D, Balaban N, Baquero F, Courvalin P, Glaser P, Gophna U . Antibiotic resistance: turning evolutionary principles into clinical reality. FEMS Microbiol Rev. 2020; 44(2):171-188. DOI: 10.1093/femsre/fuaa001. View

11.

Andersson D, Hughes D . Antibiotic resistance and its cost: is it possible to reverse resistance?. Nat Rev Microbiol. 2010; 8(4):260-71. DOI: 10.1038/nrmicro2319. View

12.

Melnyk A, Wong A, Kassen R . The fitness costs of antibiotic resistance mutations. Evol Appl. 2015; 8(3):273-83. PMC: 4380921. DOI: 10.1111/eva.12196. View

13.

Jorth P, Staudinger B, Wu X, Hisert K, Hayden H, Garudathri J . Regional Isolation Drives Bacterial Diversification within Cystic Fibrosis Lungs. Cell Host Microbe. 2015; 18(3):307-19. PMC: 4589543. DOI: 10.1016/j.chom.2015.07.006. View

14.

Lieberman T, Michel J, Aingaran M, Potter-Bynoe G, Roux D, Davis Jr M . Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes. Nat Genet. 2011; 43(12):1275-80. PMC: 3245322. DOI: 10.1038/ng.997. View

15.

Breidenstein E, de la Fuente-Nunez C, Hancock R . Pseudomonas aeruginosa: all roads lead to resistance. Trends Microbiol. 2011; 19(8):419-26. DOI: 10.1016/j.tim.2011.04.005. View

16.

Wheatley R, Diaz Caballero J, van der Schalk T, De Winter F, Shaw L, Kapel N . Gut to lung translocation and antibiotic mediated selection shape the dynamics of Pseudomonas aeruginosa in an ICU patient. Nat Commun. 2022; 13(1):6523. PMC: 9681761. DOI: 10.1038/s41467-022-34101-2. View

17.

Saber M, Donner J, Levade I, Acosta N, Parkins M, Boyle B . Single nucleotide variants in populations from sputum correlate with baseline lung function and predict disease progression in individuals with cystic fibrosis. Microb Genom. 2023; 9(4). PMC: 10210962. DOI: 10.1099/mgen.0.000981. View

18.

Wheatley R, Diaz Caballero J, Kapel N, De Winter F, Jangir P, Quinn A . Rapid evolution and host immunity drive the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection. Nat Commun. 2021; 12(1):2460. PMC: 8080559. DOI: 10.1038/s41467-021-22814-9. View

19.

Warren R, Victor T, Streicher E, Richardson M, Beyers N, Gey van Pittius N . Patients with active tuberculosis often have different strains in the same sputum specimen. Am J Respir Crit Care Med. 2004; 169(5):610-4. DOI: 10.1164/rccm.200305-714OC. View

20.

Maley C, Galipeau P, Finley J, Wongsurawat V, Li X, Sanchez C . Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet. 2006; 38(4):468-73. DOI: 10.1038/ng1768. View