Antibiotic-induced stress responses in Gram-negative bacteria and their role in antibiotic resistance

Abstract

Bacteria adapt to changes in their natural environment through a network of stress responses that enable them to alter their gene expression to survive in the presence of stressors, including antibiotics. These stress responses can be specific to the type of stress and the general stress response can be induced in parallel as a backup mechanism. In Gram-negative bacteria, various envelope stress responses are induced upon exposure to antibiotics that cause damage to the cell envelope or result in accumulation of toxic metabolic by-products, while the heat shock response is induced by antibiotics that cause misfolding or accumulation of protein aggregates. Antibiotics that result in the production of reactive oxygen species (ROS) induce the oxidative stress response and those that cause DNA damage, directly and through ROS production, induce the SOS response. These responses regulate the expression of various proteins that work to repair the damage that has been caused by antibiotic exposure. They can contribute to antibiotic resistance by refolding, degrading or removing misfolded proteins and other toxic metabolic by-products, including removal of the antibiotics themselves, or by mutagenic DNA repair. This review summarizes the stress responses induced by exposure to various antibiotics, highlighting their interconnected nature, as well the roles they play in antibiotic resistance, most commonly through the upregulation of efflux pumps. This can be useful for future investigations targeting these responses to combat antibiotic-resistant Gram-negative bacterial infections.

Figure 1.

Bacterial stress responses induced by antibiotics. (a) Oxidative stress response, (b) SOS response, (c) ESR, (d) Heat shock response, (e) General stress response. Stressors are indicated in bold red text. DSBs, double strand breaks; HR, homologous recombination; IM, inner membrane; LPS, lipopolysaccharides; MPs, misfolded proteins; NER, nucleotide excision repair; OM, outer membrane; OMPs, outer membrane proteins; OMV, outer membrane vesicle; PG, peptidoglycan; SSB, single strand breaks; TLS, translesion synthesis. Created with BioRender.com.