Antibiotic and biocide resistance in bacteria: Introduction

Abstract

1. Summary, 1S 2. Bacterial resistance to antibiotics, 1S 3. Bacterial resistance to biocides, 1S 4. Mechanisms of action of antibiotics and biocides, 2S 5. Mechanisms of bacterial resistance to antibiotics and biocides, 2S 6. Overall comments, 3S 7. References, 3S Drug resistance in bacteria is increasing and the pace at which new antibiotics are being produced is slowing. It is now almost commonplace to hear about methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multi-drug resistance in Mycobacterium tuberculosis (MDRTB) strains and multi-drug-resistant (MDR) Gram-negative bacteria. So-called new and emerging pathogens add to the gravity of the situation. Reduced susceptibility to biocides is also apparently increasing, but is more likely to be low level in nature and to concentrations well below those used in hospital, domestic an industrial practice. A particular problem, however, is found with bacteria and other micro-organisms present in biofilms, where a variety of factors can contribute to greater insusceptibility compared with cells in planktonic culture. Also of potential concern is the possibility that widespread usage of biocides is responsible for the selection and maintenance of antibiotic-resistant bacteria. The basic mechanisms of action of, and bacterial resistance to, antibiotics are generally well documented, although data continue to accumulate about the nature and importance of efflux systems. In contrast, the modes of action of most biocides are poorly understood and consequently, detailed evaluation of bacterial resistance mechanisms is often disappointing. During this Symposium, the mechanisms of bacterial resistance to antibiotics and biocides are discussed at length. It is hoped that this knowledge will be used to develop newer, more effective drugs and biocides that can be better and perhaps, on occasion, more logically used to combat the increasing problem of bacterial resistance. Bacterial resistance to antibiotics is a major therapeutic problem (6). Moreover, the pace at which new chemotherapeutic drugs are being introduced into clinical practice has slowed. It is now almost commonplace to hear about methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multi-drug resistance in Mycobacterium tuberculosis (MDRTB) strains and multi-drug-resistant (MDR) Gram-negative bacteria. Other well known examples include penicillin resistance in Neisseria gonorrhoeae, pneumococcal infections that are resistant to penicillin or macrolide therapy, and drug-resistant meningococci and Haemophilus influenzae (Table 1). The outcome is that many antibiotics can no longer be used for the treatment of infections caused by such organisms, and the threat to the usage of other drugs is steadily increasing (Table 1) (4; 3; 11; 16). The gravity of the situation is compounded by the emergence of epidemic, multi-antibiotic-resistant Burkholderia cepacia and Stenotrophomonas maltophilia (15). Reduced susceptibility to biocides is also apparently increasing (9; 13), but is more likely to be low-level in nature and to concentrations well below those used in hospital, domestic and industrial practice. In actual fact, concern about the resistance of Pseudomonas aeruginosa to cationic biocides was expressed some 50 years ago (8), with subsequent studies showing that many different types of bacteria could gradually become less susceptible to most biocides over long periods of time. This is amply demonstrated in the report by 2) in which he lists increased insusceptibility to many biocides, including quaternary ammonium compounds (QACs), chlorhexidine, phenolics, heavy metals, and even aldehydes such as glutaraldehyde. A particular problem is found with bacteria and other micro-organisms present in biofilms, where a variety of factors can contribute to the greater insusceptibility to biocides compared with cells in planktonic culture (7). This is significant not only environmentally, e.g. biofouling and biocorrosion, but also with implanted medical devices, the infection with which may be difficult to eradicate. The basic mechanisms of action of antibiotics are generally well documented (14). They act as inhibitors of peptidoglycan synthesis (e.g. β-lactams, glycopeptides), protein synthesis (tetracyclines, chloramphenicol, mupirocin, macrolides, aminoglycosides-aminocyclitols) and nucleic acid synthesis by interrupting nucleotide metabolism (sulphonamides, diaminopyrimidines), inhibiting RNA polymerase (rifamycins), or inhibiting DNA gyrase (quinolones). In addition, some antibiotics (polymyxins) interfere with membrane integrity. In mycobacteria, isoniazid has to be activated and then inhibits mycolic acid synthesis (reviewed by 17). By contrast, the mechanisms of the antibacterial action of biocides are imperfectly understood. Biocides are known to interact with bacterial cell walls or envelopes (e.g. glutaraldehyde), produce changes in cytoplasmic membrane integrity (cationic agents), dissipate the proton-motive force (pmf; organic acids and esters), inhibit membrane enzymes (thiol interactors), act as alkylating agents (ethylene oxide), cross-linking agents (aldehydes) and intercalating agents (acridines), or otherwise interact with identifiable chemical groups in the cell (5). Biocides are likely to have multiple target sites within a bacterial cell (5), although it has now been shown (10) that triclosan acts as a specific inhibitor of enoyl reductase. Mechanisms of bacterial resistance to antibiotics are well understood (11). The ways in which bacteria evade or overcome the action of drugs are too complex to describe here in detail. Essentially, they involve reduced antibiotic uptake (impermeability or efflux), drug degradation (enzymatic attack), modification of specific target sites, overproduction of the target or bypass of the antibiotic-sensitive step by duplication of the target site, the second version being insusceptible (6; 3; 12). Resistance to isoniazid in mycobacteria is primarily associated with the absence of an enzyme-metabolic pathway such that the drug is not converted intracellularly into its active form (1). Because the mechanisms of action of biocides are often poorly understood (Section 4), detailed evaluation of bacterial resistance mechanisms remains disappointing. Nevertheless, it is known that at least some (efflux, impermeability, modification of target sites) of the general mechanisms responsible for antibiotic resistance are also applicable to biocides (Table 2). The possibility exists of `cross-resistance' arising between antibiotics and biocides. The inexorable rise in antibiotic-resistant bacteria, the comparative dearth of new therapeutic agents and the apparent increase in biocide resistance paint a gloomy picture. Speakers in this symposium consider target sites (including novel ones) for antibacterial action, the mechanism of bacterial resistance, the importance of resistance in the medical, veterinary and food industries and the thorny issue of biocide usage and possible antibiotic resistance.