Solvent tolerance in bacteria: role of efflux pumps and cross-resistance with antibiotics

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Abstract

Microorganisms have mechanisms that enable them to tolerate lethal concentrations of toxic compounds. This feature has been exploited in a wide range of bioprocesses that range from bioremediation applications to production of fine chemicals in two-phase reaction media. The ability to modify the physical properties of cellular membranes has long been put forward as a protection mechanism that enables microorganisms to tolerate solvents. More recently, efflux pumps have been shown to extrude deleterious compounds, such as antibiotics, drugs and solvents. An understanding of the mechanism of solvent tolerance and its relationship to cross-resistance of pathogenic organisms to antibiotics has major impact on the type and use of disinfectants and disinfecting procedures. The presence of solvents in the growth environment may lead to the emergence of solvent resistant strains and, therefore, overuse may propagate resistant microbial variants. In this paper, mechanisms that lead to solvent tolerance of microbes and accompanying specific antibiotic resistance are reviewed.

Introduction

Microorganisms are currently exposed to deleterious chemicals naturally occurring in the environment, for example, natural antibiotics, produced by members of microbial communities and detergents such as bile salts, present in the intestinal tract of higher animals. Human activity has further led to the emergence of a plethora of noxious chemicals, either inorganic or organic (xenobiotics) concomitant to industrial activities. Others are chemicals specifically developed to act as antimicrobial agents, such as semisynthetic antibiotics or biocides. The target of the toxic compound may be the cell wall, the cytoplasmic membrane or the biosynthetic pathway of protein and nucleic acid synthesis. The antimicrobial compound may affect the structure of biomembranes or impair biosynthetic pathways essential for microbial growth. Nevertheless, bacteria display outstanding resistance to the action of toxic compounds because of intrinsic long-standing mechanisms that protect cells from continuous exposure to harmful chemicals. In addition to with the metabolism of antimicrobials into non-toxic compounds [1], [2], [3] and the modification of the target site of action [4], the presence of broadly-specific efflux pumps that reduce the concentration of antimicrobials in the cytoplasm to sub-toxic levels has been acknowledged as a major route for microbial resistance to toxic compounds [5], [6], [7]. Although these efflux pumps have been known for some time, its relevance has only recently been acknowledged, particularly since such drug extrusion mechanisms are a major cause of intrinsic bacterial resistance to antibiotics. It is, therefore, logical that most research work in this field has focused on antibiotic efflux pumps [5], [8], [9]. However, it has been clearly shown that some microbial strains, such as Pseudomonas aeruginosa, are tolerant to structurally unrelated antimicrobial agents, such as antibiotics, organic solvents and biocides [9], [10], [11]. The overuse of antibiotics, the escalating use of household products containing biocide agents, and the emission of toxic wastes contribute to the development of drug- and solvent-resistant strains [12], [13], [14], [15], [16], [17], [18], [19], [20]. A deeper insight on the mechanisms of solvent tolerance and its relation to antibiotic tolerance may contribute to broaden the overall knowledge on the inherent properties of bacterial resistance to toxic agents. It may also provide a better approach for the design of new antimicrobial synthetic drugs and biocides, as well as strategies for disinfection procedures, since organic solvents are classical antimicrobial agents [21]. This paper reviews data gathered on microbial tolerance to organic solvents and its relation to antibiotic resistance.

Section snippets

Microbial resistance to organic solvents

The toxicity of an organic solvent is evaluated according to its log Pow (logarithm of the partition coefficient of the solvent in a standard n-octanol/water system). Solvents with log Pow above 5 are biocompatible, whereas solvents with log Pow between 1 and 5 are toxic [22], [23], [24], [25]. Gram-negative bacteria are slightly more tolerant than Gram-positive bacteria. This effect is due to the outer membrane of Gram-negative bacteria which acts as an barrier, particularly to the penetration

Conclusions and perspectives

Efflux pumps play a major role on solvent tolerance in bacteria. Often these protective mechanisms overlap their substrates along a wide range of structurally diverse chemicals. Understanding of the mechanisms of individual and cross resistance may provide effective clues for the design of more effective antimicrobials, combined with a more efficient methodology for the use of known antimicrobials. It may also pave the way for the application of strains tolerant to noxious chemicals in other

Acknowledgements

We thank Professor Leonard Amaral for helpful comments and suggestions. We would also like to thank Dr Miguel Viveiros for helpful discussions.

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