Trends in Microbiology
ReviewStress responses as determinants of antimicrobial resistance in Gram-negative bacteria
Section snippets
Environmental impacts on bacterial antimicrobial susceptibility
It has been known for some time that in vivo susceptibility of bacteria to antimicrobials does not always match in vitro efficacy [1] and that mutational expression of antimicrobial resistance mechanisms can be selected in the absence of antimicrobial exposure [2], indications that environmental conditions can and do impact upon antimicrobial resistance in bacteria. Nutrient limitation is a classic example of this, where Mg2+ limitation promotes resistance to cationic antimicrobials such as
Oxidative and nitrosative stresses and antimicrobial resistance
A variety of antimicrobial resistance determinants and/or their regulatory proteins are affected by oxidative or nitrosative stress (Table 1). A key and long-known regulator of an oxidative stress response in E. coli and other enteric organisms is SoxRS, originally defined as a superoxide (O2–)-responsive two-component regulatory system (TCS) that controlled an adaptive O2– stress response, because it was activated by redox-cycling agents (e.g. paraquat) that generated O2– inside aerobically
The stringent response and antimicrobial resistance
A classic example of nutritional stress is amino acid deprivation, which stimulates what has long been known as the stringent response (SR) 40, 41 (Box 1). Activated by a variety of nutritional stresses that compromise cell growth (depletion of iron, phosphate, carbon source or fatty acids) [41], the SR is associated with increased production of guanosine 5′-(tri)diphosphate, 3′-diphosphate [(p)ppGpp] [42], which has a myriad of effects on bacterial cell physiology and, perhaps not
Envelope stress and antimicrobial resistance
Environmental affronts to cell envelope (membranes and cell wall) structure and function are met with bacterial adaptive responses that are intended to permit survival in the face of membrane and/or cell wall perturbation. These so-called envelope stress responses are highly-regulated, typically by alternative sigma factors referred to as extracytoplasmic function (ECF) sigmas {e.g. RpoE (σE) in E. coli and other organisms [43]} and TCSs (e.g. AmgRS in P. aeruginosa [44] and CpxRA in E. coli
Heat shock and antimicrobial resistance
Aminoglycoside induction of heat shock genes has been reported in E. coli [54], Acinetobacter baumannii [55] and P. aeruginosa [56]. In the case of P. aeruginosa, this is mediated by the alternate Lon protease, AsrA, whose expression is induced in response to the aminoglycoside tobramycin or heat shock, and is dependent upon the RpoH heat shock sigma factor [56]. Intriguingly, asrA overexpression in an engineered strain had a modest positive impact upon aminoglycoside resistance [56], raising
Stress-induced mutagenesis and antimicrobial resistance
In the face of ‘growth-limiting’ stress owing to nutrient starvation, hypoxia, low pH, increased osmotic pressure, extreme temperature shifts or antimicrobial exposure, bacteria activate a stress-induced increase in the mutation rate (reviewed in 12, 59). Also termed adaptive mutagenesis, stress-induced mutagenesis arises from a stress-dependent introduction of double-strand breaks into chromosomal DNA [60] and subsequent activation of error-prone repair under the control of the SOS response
Persisters as a stress response
The ability of a small subpopulation of an apparently susceptible and genetically homogenous population of bacteria to survive antibiotic exposure has been known for some time 69, 70. These so-called persisters are slow-growing or dormant organisms, and slow growth and dormancy effectively protects them from the lethal impact of antibiotics, which act preferentially on rapidly growing bacteria [70]. Persisters are an example of the phenotypic heterogeneity that exists naturally within
Stress-induced biofilm formation
Bacteria commonly exist as biofilms in nature and in the infected host [78], and these structures provide resistance to antimicrobials among other benefits [79]. Thus, environmental factors that promote bacterial biofilm formation will positively contribute to antimicrobial resistance. A variety of stresses have been linked to biofilm formation, and biofilm formation is itself possibly a stress response [80]. The observation, for example, that inactivating mutations in the rpoS gene encoding
Concluding remarks
Despite the direct link between stress and known antimicrobial-resistance determinants in many instances, the function of the resistance genes in the stress response itself are for the most part unknown or unconfirmed. Although several of the RND family of multidrug exporters of P. aeruginosa are inducible, for example, by oxidative (MexXY-OprM, MexAB-OprM), nitrosative (MexEF-OprN) and envelope (MexCD-OprJ) stress, their roles in the corresponding stress responses and the identities of the
Acknowledgments
Work in the author's laboratory on environmental influences on antimicrobial resistance in P. aeruginosa is supported by operating grants from the Canadian Institutes of Health Research and Cystic Fibrosis Canada.
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