The evolution of heteroresistance via small colony variants in Escherichia coli following long term exposure to bacteriostatic antibiotics

• Published in: Nature communications Vol. 15; no. 1; pp. 7936 - 9
• Main Authors: Gil-Gil, Teresa, Berryhill, Brandon A., Manuel, Joshua A., Smith, Andrew P., McCall, Ingrid C., Baquero, Fernando, Levin, Bruce R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 38/23; 631/181/2475; 631/326/22/1290; 631/326/22/1434; Anti-Bacterial Agents - pharmacology; Antibiotics; Azithromycin; Azithromycin - pharmacology; Bacteria; Bacteriostasis; Bacteriostats; Chloramphenicol; Chloramphenicol - pharmacology; Chloromycetin; Coliforms; Colonies; Drug delivery; Drug Resistance, Bacterial - drug effects; Drug Resistance, Bacterial - genetics; Drug Resistance, Multiple, Bacterial - drug effects; Drug Resistance, Multiple, Bacterial - genetics; Drugs; E coli; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - genetics; Evolution; Exposure; Humanities and Social Sciences; Microbial Sensitivity Tests; multidisciplinary; Populations; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52166-z

Traditionally, bacteriostatic antibiotics are agents able to arrest bacterial growth. Despite being traditionally viewed as unable to kill bacterial cells, when they are used clinically the outcome of these drugs is frequently as effective as when a bactericidal drug is used. We explore the dynamics of Escherichia coli after exposure to two ribosome-targeting bacteriostatic antibiotics, chloramphenicol and azithromycin, for thirty days. The results of our experiments provide evidence that bacteria exposed to these drugs replicate, evolve, and generate a sub-population of small colony variants (SCVs) which are resistant to multiple drugs. These SCVs contribute to the evolution of heteroresistance and rapidly revert to a susceptible state once the antibiotic is removed. Stated another way, exposure to bacteriostatic drugs selects for the evolution of heteroresistance in populations previously lacking this trait. More generally, our results question the definition of bacteriostasis as populations exposed to bacteriostatic drugs are replicating despite the lack of net growth. Traditionally, bacteriostatic antibiotics were thought to simply arrest bacterial growth. In this work, the authors explore the dynamics of Escherichia coli when exposed to bacteriostatic antibiotics, finding that long-term exposure to bacteriostatic antibiotics favors the evolution of heteroresistant small colony variants.