Bacterial Efflux Pumps

Bacteria and cancer cells develop resistance to more than one agent as a consequence of being exposed to ineffective levels of the agent for a prolonged period of time. The resistance of these cells is mediated by over-expressed efflux pumps that have the ability to extrude a large variety of unrelated chemicals. This review discusses the main types of multidrug resistant (MDR) efflux systems of bacteria and cancer cells, and shows the similarity of specific efflux systems between them with respect to given agents that inhibit efflux, thus rendering these cells once more susceptible to agents to which they had developed MDR. Despite the huge range of available antibiotics, numbering in thousands, mortality caused by bacteria continues to escalate in both economically favoured and disadvantaged countries. Globally, respiratory infections caused by nonmycobacteria and Mycobacterium tuberculosis kill over four million people world-wide and those bacteria that cause diarrhoeal disease kill an additional 1.75 million per year (1). Globally, over 20% of all deaths result from bacterial infections (2). The rates of bacterial infections and ensuing mortality are expected to rise dramatically due to the emergence of HIV infections world-wide and subsequent development of AIDS. Although bacterial infections are of great concern, they are not the major health threat encountered globally. According to the WHO Global Report on Cancer 2000 (3), 6 million deaths were caused by cancer world-wide. More disturbing is the prediction made by the WHO, namely that by the year 2020 at least 15 million will die from cancer (3). Why are global bacterial infections on the rise despite the availability of a large and ever-increasing gamut of antibiotics? The advent of AIDS and the predisposition of this viral infection to co-infection by bacteria is, of course, part of the problem. But as of the time writing, it is minor in comparison to the problem of emerging resistance of bacterial pathogens. As an example, the sensitivity of Staphylococcus aureus to the first natural antibiotic, penicillin, was essentially 100% in the early 1950’s. However, within the span of one decade, resistance to the beta-lactam methicillin was evident; today, 60 to 80% of all clinical isolates of Staphylococcus aureus are resistant to methicillin (oxacillin) (4). Acquisition of methicillin resistant S. aureus (MRSA), once thought to be nosocomially mediated, is now known to have part of its origin in the community (5-8). The period of time for global development of resistance to oxacillin by Staphylococcus aureus was exceeded by the organism’s resistance to fluoroquinolones, namely within a few years (9), making this antibiotic relatively useless today. The problem of antibiotic resistance of Staphylococcus aureus has become more acute now that resistance to the last drug of defence, vancomycin, is increasing (10). Although antibiotic resistance is now common for all important pathogenic bacteria (11), multidrug resistance (MDR) of Mycobacterium tuberculosis (9, 10, 12), Gramnegative bacteria (13), enterococci (14), streptococci (15) and the like have seriously affected the selection of therapeutic modality. Bacterial Efflux Pumps All living cells contain genes that code for proteins which make up efflux pumps that have the capacity to extrude 237 Correspondence to: Leonard Amaral, Unit of Mycobacteriology / UPMM, Institute of Hygiene and Tropical Medicine Universidade Nova de Lisboa, Rua da Junqueira 96, 1349-008 Lisbon, Portugal. Tel: +351 21 3652600, Fax: +351 21 3632105, e-mail: lamaral@ ihmt.unl.pt