Bacterial Multidrug Resistance Mediated by a Homologue of the Human Multidrug Transporter P‐glycoprotein

Abstract

SummaryMost ATP-binding cassette (ABC) multidrug transporters known to date are of eukaryotic origin, such as the P-glycoproteins (Pgps) and multidrug resistance-associated proteins (MRPs). Only one well-characterized ABC multidrug transporter, LmrA, is of bacterial origin. On the basis of its structural and functional characteristics, this bacterial protein is classified as a member of the P-glycoprotein cluster of the ABC transporter superfamily. LmrA can even substitute for P-glycoprotein in human lung fibroblast cells, suggesting that this type of transporter is conserved from bacteria to man. The functional similarity between bacterial LmrA and human P-glycoprotein is further exemplified by their currently known spectrum of substrates, consisting mainly of hydrophobic cationic compounds. In addition, LmrA was found to confer resistance to eight classes of broad-spectrum antibiotics, and homologs of LmrA have been found in pathogenic bacteria, supporting the clinical and academic value of studying this bacterial protein. Current studies are focused on unraveling the mechanism by which ABC multidrug transporters, such as LmrA, couple the hydrolysis of ATP to the translocation of drugs across the membrane. Recent evidence indicates that LmrA mediates drug transport by an alternating two-site transport mechanism. IUBMB Life, 53: 213-218, 2002

Efflux-mediated antimicrobial resistance

“…While LmrA is not relevant clinically, occurring as it does in a milk spoilage organism, it is noteworthy for its very broad range of substrates that include, in addition to fluoroquinolones, numerous clinically-relevant antimicrobials, 85 and its functional similarly to P-glycoprotein, the mammalian multidrug transporter. 239 An in vitro-selected ethidium bromide-resistant mutant of Mycoplasma hominis displaying a multidrug-resistant phenotype and reduced ciprofloxacin accumulation was shown to overexpress two genes encoding a putative ABC type efflux, 240,241 another example, then, of a bacterial ABC exporter accommodating fluoroquinolones.…”

Antibiotic resistance in lactococci and enterococci: phenotypic and molecular-genetic aspects

“…This multidrug transporter functions as a homodimer and realizes resistance to aminoglycosides, cephalosporins, macrolides, penicillins, quinolones, streptogramins and tetracyclines (73). Genome sequencing revealed homologs of LmrA in different genera of bacteria: Oenococcus oeni, Escherichia coli, Bacillus subtilis, Helicobacter pylori, Mycobacterium genitalium, Haemophilus influenza, S. aureus (74)(75)(76)(77). LmrP belongs to the MFS family and confers resistance to a broad range of clinically important antibiotics: lincosamides, tetracyclines, streptogramins, 14-and 15-membered macrolides.…”

Modulation of Bacterial Multidrug Resistance Efflux Pumps of the Major Facilitator Superfamily

“…Based on the modes of energy, amino acid sequence similarities, predicted secondary protein structures, known 3D crystal protein structures, and phylogenetic relationships, bacterial drug efflux transporters are classified into five different major superfamilies and are shown in Figure 2: (i) the major facilitator superfamily (MFS) [58, 71]; (ii) the ATP-binding cassette (ABC) superfamily [72, 73]; (iii) the small multidrug resistance (SMR) superfamily [74]; (iv) the resistance-nodulation-cell division (RND) superfamily [75, 76]; and (v) the multidrug and toxic compound extrusion superfamily (MATE) of transporters [69]. …”