Chapter 11 : Antibiotic Resistance via Membrane Efflux Pumps

Schematic of the AcrAB-TolC tripartite protein efflux pumps that span the inner membrane, periplasm, and outer membrane in Gram-negative bacteria. (Image created using PyMOL from PDB files 1EK9 [TolC], 2F1M [AcrA], and 1IWG [AcrB] following a literature model of the efflux pump [Piddock, 2006a].)

Three types of alterations to the OprD outer membrane porin of Pseudomonas strains. (Adapted from Fernandez and Hancock [2012].)

Tetracycline as a ligand for repressor TetR drives transcriptional activation of the TetA efflux pump for tetracycline. (Adapted from Billouris et al. [2011].)

Five families of bacterial membrane efflux pumps. Examples of solutes pumped out by each efflux family are shown. The RND family is shown as a tripartite pump in Gram-negative bacteria to transit both inner and outer membranes. The ABC transporter family uses ATP hydrolysis to drive efflux. The other four pump families (MFS, MATE, SMR, and RND) use proton pumping in one direction while the antibiotic/xenobiotic is pumped from inside to outside the membrane. (Reprinted from Piddock [2006a] with permission.)

Schematic diagrams of bacterial inner membrane transporters: helical LacY protein transports lactose, and GLUT1 imports glutamate. (Reprinted from Henderson and Baldwin [2012] with permission.)

(a) Diagram of the three-component AcrAB-TolC pump from Gram-negative bacteria. AcrB is in the inner membrane, and AcrA is in the periplasm, bridging between AcrB and TolC. TolC has cytoplasmic domains that interface with AcrA and a β-barrel domain that traverses the outer membrane. (b) The TolC outer membrane component can also couple to ATP-dependent export pumps, as shown for HlyBD. The pore of TolD can open and close in different conformations to represent open and closed states of the outer membrane component of the tripartite pump. (Reprinted from Hinchliffe et al. [2013] with permission.)

The regulation of different sets of tripartite efflux pumps can be controlled by a mixture of global and local signals in pseudomonads. Abbreviations in the bottom line of the figure summarize antibiotics pumped out by the different pump combinations. The top of the figure indicates molecules that affect efflux pump gene regulation including C4-HSL, AMP, and ROS. AG, aminoglycoside; AMP, antimicrobial peptides; BL, beta-lactam; CA, carbapenems; CI, ciprofloxacin; CM, chloramphenicol; CP, cationic peptides; EM, erythromycin; FQ, fluoroquinolone; IM, inner membrane; OM, outer membrane; ML, macrolides; NB, novobiocin; ROS, reactive oxygen species; TC, tetracycline; TI, ticarcillin; TM, trimethoprim. (Reprinted from Fernandez and Hancock [2012] with permission.)

A subset of molecular scaffolds that have been identified as blockers of one or more bacterial efflux pumps.