Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria
01 Apr 2006-Clinical Microbiology Reviews (American Society for Microbiology)-Vol. 19, Iss: 2, pp 382-402
TL;DR: This review focuses on chromosomally encoded pumps in bacteria that cause infections in humans, and suggests that resistance nodulation division systems are important in pathogenicity and/or survival in a particular ecological niche.
Abstract: Efflux pump genes and proteins are present in both antibiotic-susceptible and antibiotic-resistant bacteria. Pumps may be specific for one substrate or may transport a range of structurally dissimilar compounds (including antibiotics of multiple classes); such pumps can be associated with multiple drug (antibiotic) resistance (MDR). However, the clinical relevance of efflux-mediated resistance is species, drug, and infection dependent. This review focuses on chromosomally encoded pumps in bacteria that cause infections in humans. Recent structural data provide valuable insights into the mechanisms of drug transport. MDR efflux pumps contribute to antibiotic resistance in bacteria in several ways: (i) inherent resistance to an entire class of agents, (ii) inherent resistance to specific agents, and (iii) resistance conferred by overexpression of an efflux pump. Enhanced efflux can be mediated by mutations in (i) the local repressor gene, (ii) a global regulatory gene, (iii) the promoter region of the transporter gene, or (iv) insertion elements upstream of the transporter gene. Some data suggest that resistance nodulation division systems are important in pathogenicity and/or survival in a particular ecological niche. Inhibitors of various efflux pump systems have been described; typically these are plant alkaloids, but as yet no product has been marketed.
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TL;DR: A review of antibiotic resistance development over the past half-century can be found in this article, with the oft-restated conclusion that it is time to act and to restore the therapeutic applications of antibiotics.
Abstract: Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man's overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clinically, agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory.
4,364 citations
TL;DR: This review details the significant advances that have been made in understanding of this remarkable organism over the last 10 years, including current taxonomy and species identification, issues with susceptibility testing, mechanisms of antibiotic resistance, global epidemiology, clinical impact of infection, host-pathogen interactions, and infection control and therapeutic considerations.
Abstract: Acinetobacter baumannii has emerged as a highly troublesome pathogen for many institutions globally. As a consequence of its immense ability to acquire or upregulate antibiotic drug resistance determinants, it has justifiably been propelled to the forefront of scientific attention. Apart from its predilection for the seriously ill within intensive care units, A. baumannii has more recently caused a range of infectious syndromes in military personnel injured in the Iraq and Afghanistan conflicts. This review details the significant advances that have been made in our understanding of this remarkable organism over the last 10 years, including current taxonomy and species identification, issues with susceptibility testing, mechanisms of antibiotic resistance, global epidemiology, clinical impact of infection, host-pathogen interactions, and infection control and therapeutic considerations.
2,915 citations
Cites background from "Clinically Relevant Chromosomally E..."
...Unfortunately, progress has been slow, with agents such as phenyl-arginine-naphthylamide doing well when assessed in vitro but coming to demise due to toxicity concerns (433)....
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...Through large-scale in vitro screening, a range of efflux pump inhibitors have been identified, with the majority being plant alkaloids (433) but, more recently, also synthetic compounds (43)....
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TL;DR: Recent advances in understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics are reviewed, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.
Abstract: Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.
2,837 citations
TL;DR: This chapter will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice, providing specific examples in relevant bacterial pathogens.
Abstract: The discovery, commercialization, and routine administration of antimicrobial compounds to treat infections revolutionized modern medicine and changed the therapeutic paradigm. Indeed, antibiotics have become one of the most important medical interventions needed for the development of complex medical approaches such as cutting-edge surgical procedures, solid organ transplantation, and management of patients with cancer, among others. Unfortunately, the marked increase in antimicrobial resistance among common bacterial pathogens is now threatening this therapeutic accomplishment, jeopardizing the successful outcomes of critically ill patients. In fact, the World Health Organization has named antibiotic resistance as one of the three most important public health threats of the 21st century (
1
).
1,429 citations
TL;DR: Evidence is presented that multidrug-resistance efflux pumps have roles in bacterial pathogenicity and it is proposed that these pumps therefore have greater clinical relevance than is usually attributed to them.
Abstract: 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.
1,367 citations
References
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TL;DR: This review summarizes the development in the field since the previous review and begins to understand how this bilayer of the outer membrane can retard the entry of lipophilic compounds, owing to increasing knowledge about the chemistry of lipopolysaccharide from diverse organisms and the way in which lipopoly Saccharide structure is modified by environmental conditions.
Abstract: Gram-negative bacteria characteristically are surrounded by an additional membrane layer, the outer membrane. Although outer membrane components often play important roles in the interaction of symbiotic or pathogenic bacteria with their host organisms, the major role of this membrane must usually be to serve as a permeability barrier to prevent the entry of noxious compounds and at the same time to allow the influx of nutrient molecules. This review summarizes the development in the field since our previous review (H. Nikaido and M. Vaara, Microbiol. Rev. 49:1-32, 1985) was published. With the discovery of protein channels, structural knowledge enables us to understand in molecular detail how porins, specific channels, TonB-linked receptors, and other proteins function. We are now beginning to see how the export of large proteins occurs across the outer membrane. With our knowledge of the lipopolysaccharide-phospholipid asymmetric bilayer of the outer membrane, we are finally beginning to understand how this bilayer can retard the entry of lipophilic compounds, owing to our increasing knowledge about the chemistry of lipopolysaccharide from diverse organisms and the way in which lipopolysaccharide structure is modified by environmental conditions.
3,585 citations
"Clinically Relevant Chromosomally E..." refers background in this paper
...coli and other Enterobacteriaceae, there are porin proteins present in the outer membrane (139)....
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...The substrate profile of the AcrAB-TolC pump includes chloramphenicol, lipophilic -lactams, fluoroquinolones, tetracycline, rifampin, novobiocin, fusidic acid, nalidixic acid, ethidium bromide, acriflavine, bile salts, short-chain fatty acids, SDS, Triton X-100, and triclosan (46, 139, 149, 216, 230)....
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TL;DR: The antimicrobial actions of bile are described, the variations in bile tolerance between bacterial genera are assessed and the relationship between bile and virulence is examined.
Abstract: Commensal and pathogenic microorganisms must resist the deleterious actions of bile in order to survive in the human gastrointestinal tract. Herein we review the current knowledge on the mechanisms by which Gram-positive and Gram-negative bacteria contend with bile stress. We describe the antimicrobial actions of bile, assess the variations in bile tolerance between bacterial genera and examine the interplay between bile stress and other stresses. The molecular mechanisms underlying bile tolerance are investigated and the relationship between bile and virulence is examined. Finally, the potential benefits of bile research are briefly discussed.
1,467 citations
"Clinically Relevant Chromosomally E..." refers background in this paper
...jejuni that mutants lacking components of the AcrAB-TolC pump or the CmeABC pump are hypersusceptible to bile and bile salts (natural antimicrobial substances produced in the avian and mammalian gut as an antimicrobial defense to bacterial challenge) and that mutants that overexpress components of these pumps are resistant to high concentrations of bile and bile salts (16, 92, 100, 101, 111, 176, 217)....
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TL;DR: Given the increasing multidrug resistance among staphylococci and the possible emergence of vancomycin-resistant strains, global strategies are needed to control emergence and spread of multiply resistant staphlyococci.
Abstract: Between January 1997 and December 1999, bloodstream isolates from 15,439 patients infected with Staphylococcus aureus and 6350 patients infected with coagulase-negative Staphylococcus species (CoNS) were referred by SENTRY-participating hospitals in the United States, Canada, Latin America, Europe, and the Western Pacific region. S. aureus was found to be the most prevalent cause of bloodstream infection, skin and soft-tissue infection, and pneumonia in almost all geographic areas. A notable increase in methicillin (oxacillin) resistance among community-onset and hospital-acquired S. aureus strains was observed in the US centers. The prevalence of methicillin (oxacillin)-resistant S. aureus varied greatly by region, site of infection, and whether the infection was nosocomial or community onset. Rates of methicillin resistance were extremely high among S. aureus isolates from centers in Hong Kong and Japan. Uniformly high levels of methicillin resistance were observed among CoNS isolates. Given the increasing multidrug resistance among staphylococci and the possible emergence of vancomycin-resistant strains, global strategies are needed to control emergence and spread of multiply resistant staphylococci.
1,397 citations
"Clinically Relevant Chromosomally E..." refers background in this paper
...Many MRSA strains then evolved to become resistant to fluoroquinolones and became widely disseminated, such that for some countries the predominant clones of MRSA are often fluoroquinolone resistant (39)....
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TL;DR: Fluoroquinolones and β-lactams of the latest generations are likely to select for overproduction mutants of these pumps and make the bacteria resistant in one step to practically all classes of antibacterial agents.
Abstract: 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.
1,118 citations
TL;DR: The structure of TolC is reported, revealing a distinctive and previously unknown fold that provides an explanation of how the cell cytosol is connected to the external environment during export, and suggests a general mechanism for the action of bacterial efflux pumps.
Abstract: Diverse molecules, from small antibacterial drugs to large protein toxins, are exported directly across both cell membranes of gram-negative bacteria. This export is brought about by the reversible interaction of substrate-specific inner-membrane proteins with an outer-membrane protein of the TolC family, thus bypassing the intervening periplasm. Here we report the 2.1-A crystal structure of TolC from Escherichia coli, revealing a distinctive and previously unknown fold. Three TolC protomers assemble to form a continuous, solvent-accessible conduit--a 'channel-tunnel' over 140 A long that spans both the outer membrane and periplasmic space. The periplasmic or proximal end of the tunnel is sealed by sets of coiled helices. We suggest these could be untwisted by an allosteric mechanism, mediated by protein-protein interactions, to open the tunnel. The structure provides an explanation of how the cell cytosol is connected to the external environment during export, and suggests a general mechanism for the action of bacterial efflux pumps.
1,066 citations
Additional excerpts
...OprM has 35% similarity with TolC....
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...aeruginosa MexA, MexB, and OprM (3, 4, 59, 86, 133) (Fig....
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...Structural Biology Several publications have described the crystal structures of components of the tripartite RND multidrug efflux pumps of gram-negative bacteria, including E. coli AcrB and TolC and P. aeruginosa MexA, MexB, and OprM (3, 4, 59, 86, 133) (Fig....
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...They also concluded that the -helical hairpin is directed toward OprM/TolC and the -barrel toward MexB/AcrB....
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...Ziha-Zarifi et al. (237) showed that 11 patients had MDR P. aeruginosa that overexpressed the MexAB-OprM pump....
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