Abstract
Different weak organic acids have significant potential as topical treatments for wounds infected by opportunistic pathogens that are recalcitrant to standard treatments. These acids have long been used as bacteriostatic compounds in the food industry, and in some cases are already being used in the clinic. The effects of different organic acids vary with pH, concentration, and the specific organic acid used, but no studies to date on any opportunistic pathogens have examined the detailed interactions between these key variables in a controlled and systematic way. We have therefore comprehensively evaluated the effects of several different weak organic acids on growth of the opportunistic pathogen Pseudomonas aeruginosa. We used a semi-automated plate reader to generate growth profiles for two different strains (model laboratory strain PAO1 and clinical isolate PA1054 from a hospital burns unit) in a range of organic acids at different concentrations and pH, with a high level of replication for a total of 162,960 data points. We then compared two different modeling approaches for the interpretation of this time-resolved dataset: parametric logistic regression (with or without a component to include lag phase) vs. non-parametric Gaussian process (GP) regression. Because GP makes no prior assumptions about the nature of the growth, this method proved to be superior in cases where growth did not follow a standard sigmoid functional form, as is common when bacteria grow under stress. Acetic, propionic and butyric acids were all more detrimental to growth than the other acids tested, and although PA1054 grew better than PAO1 under non-stress conditions, this difference largely disappeared as the levels of stress increased. As expected from knowledge of how organic acids behave, their effect was significantly enhanced in combination with low pH, with this interaction being greatest in the case of propionic acid. Our approach lends itself to the characterization of combinatorial interactions between stressors, especially in cases where their impacts on growth render logistic growth models unsuitable.
Highlights
Bacterial stress responses are affected by the precise nature of the stress and the environment in which it occurs, detailed studies on the impact of systematically varying the factors that affect stress responses are rarely reported
Planktonic growth was measured for two strains of Pseudomonas aeruginosa: the widely used laboratory strain PAO1 (ATCC 15692), and Pseudomonas aeruginosa PA1054, a strain resistant to multiple antibiotics isolated from a patient in the burns unit at the Queen Elizabeth II hospital in Birmingham (Halstead et al, 2015)
The treatment of infections with antimicrobial agents in addition to or in combination with antibiotics is likely to increase in coming years
Summary
Bacterial stress responses are affected by the precise nature of the stress and the environment in which it occurs, detailed studies on the impact of systematically varying the factors that affect stress responses are rarely reported. It means that in many cases we lack both data and robust analytical tools that could reveal interactions between different factors, and how these might influence the ability of the organism to survive or grow in the stressful environment This information is valuable both because it can lead to greater insights into the mechanism of the stress, and because it can have applied implications in (for example) optimizing strain construction and growth conditions for biotechnological processes, or designing effective strategies for removal of a particular organism or organisms. This latter point is relevant given the pressing need to develop methods to reduce the use of antibiotics, and to treat organisms which may be resistant to multiple antibiotics. Alternative topical treatments are being sought for clinical use
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