Infectious Diseases Society of America.

Most antibiotic resistance mechanisms are associated with a fitness cost that is typically observed as a reduced bacterial growth rate. The magnitude of this cost is the main biological parameter that influences the rate of development of resistance, the stability of the resistance and the rate at which the resistance might decrease if antibiotic use were reduced. These findings suggest that the fitness costs of resistance will allow susceptible bacteria to outcompete resistant bacteria if the selective pressure from antibiotics is reduced. Unfortunately, the available data suggest that the rate of reversibility will be slow at the community level. Here, we review the factors that influence the fitness costs of antibiotic resistance, the ways by which bacteria can reduce these costs and the possibility of exploiting them.

Antibiotic resistance and its cost: is it possible to reverse resistance?

Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed.

Antibiotics and Bacterial Resistance in the 21st Century

Molecular Mechanisms of Antibacterial Multidrug Resistance

It is well established that multidrug-resistance efflux pumps encoded by bacteria can confer clinically relevant resistance to antibiotics. It is now understood that these efflux pumps also have a physiological role(s). They can confer resistance to natural substances produced by the host, including bile, hormones and host-defence molecules. In addition, some efflux pumps of the resistance nodulation division (RND) family have been shown to have a role in the colonization and the persistence of bacteria in the host. Here, I present the accumulating evidence that multidrug-resistance efflux pumps have roles in bacterial pathogenicity and propose that these pumps therefore have greater clinical relevance than is usually attributed to them.

Multidrug-resistance efflux pumps ? not just for resistance

Drug efflux pumps play a key role in drug resistance and also serve other functions in bacteria. There has been a growing list of multidrug and drug-specific efflux pumps characterized from bacteria of human, animal, plant and environmental origins. These pumps are mostly encoded on the chromosome, although they can also be plasmid-encoded. A previous article in this journal provided a comprehensive review regarding efflux-mediated drug resistance in bacteria. In the past 5 years, significant progress has been achieved in further understanding of drug resistance-related efflux transporters and this review focuses on the latest studies in this field since 2003. This has been demonstrated in multiple aspects that include but are not limited to: further molecular and biochemical characterization of the known drug efflux pumps and identification of novel drug efflux pumps; structural elucidation of the transport mechanisms of drug transporters; regulatory mechanisms of drug efflux pumps; determining the role of the drug efflux pumps in other functions such as stress responses, virulence and cell communication; and development of efflux pump inhibitors. Overall, the multifaceted implications of drug efflux transporters warrant novel strategies to combat multidrug resistance in bacteria.

Efflux-Mediated Drug Resistance in Bacteria

The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

Efflux-mediated drug resistance in bacteria: an update.

Pseudomonas aeruginosa is a major opportunistic pathogen that exhibits high-level intrinsic and acquired multiple antimicrobial resistance. In addition to the accumulation of individual drug-specific resistance mechanisms, such resistance phenotypes are attributed to the interplay between the polyspecific multidrug efflux pumps and the low outer membrane permeability, and this reflects evolution of P. aeruginosa in exposure to diverse hostile environments. A dozen drug efflux pumps, which belong to the resistance-nodulation-cell division (RND) superfamily, have been characterized in P. aeruginosa. Several RND pumps, as represented by MexAB-OprM and MexXY, play important roles in clinically relevant resistance, stress responses, and virulence. Regulation of these pumps is often under the control of local regulators (repressors or activators), global regulators, two-component regulatory systems, and modulators, whose mutations produce elevated antimicrobial resistance in many clinical isolates. This chapter provides an up-to-date overview of antimicrobial drug efflux pumps in P. aeruginosa with a focus on their substrates, regulation, inhibition, and clinical significance.

Antimicrobial Drug Efflux Pumps in Pseudomonas aeruginosa

Bacterial active efflux of drugs (encoded by plasmids) was first discovered in Escherichia coli. Subsequently, a large number of chromosomally encoded multidrug efflux pumps (represented by AcrAB-TolC system) were identified in this species. Several of these efflux systems have served as prototypical pumps for characterizing substrate specificity, transport mechanisms, regulation, and inhibition of bacterial drug transporters. Efflux pumps are encoded by chromosomes or plasmids and exhibit a variable (broad or narrow) drug substrate profile that can be clinically relevant. Physiological roles of certain pumps have been demonstrated. This chapter provides an updated overview of more than 20 individual efflux systems/pumps of various families in E. coli with a focus on their substrate profiles, clinical relevance, and expression-based regulation. A discussion is also made on the interplay between the AcrAB pump and outer membrane permeability barrier on drug susceptibility as well as the AcrB-catalyzed efflux kinetics for β-lactams in intact cells.

Xian-Zhi Li

Papers

Efflux-Mediated Drug Resistance in Bacteria

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

Efflux-mediated drug resistance in bacteria: an update.

Antimicrobial Drug Efflux Pumps in Pseudomonas aeruginosa

Antimicrobial Drug Efflux Pumps in Escherichia coli