Bacterial Multidrug Transporters: Molecular and Clinical Aspects

Lomovskaya, Olga; Zgurskaya, Helen I.; Bostian, Keith A.

doi:10.1002/9783527627424.ch5

Cited by 9 publications

(7 citation statements)

References 168 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several classes of EPIs have been reported in the literature and are being pursued in drug development programs. 112–116 Phenylalanyl-arginyl- β -naphthylamide and analogous arylamines are broad-spectrum EPIs with activities against Gram-negative bacteria; 113,117,118 arylpiperidines 119 and more recently pyrinopyridine 120 are inhibitors of AcrAB-TolC from E. coli . Likewise, pyridopyrimidines are specific inhibitors of P. aeruginosa MexB and E. coli AcrB.…”

Section: Approaches To Bypass or Break The Permeability Barriermentioning

confidence: 99%

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

2015

Self Cite

View full text Add to dashboard Cite

Gram-negative bacteria are intrinsically resistant to many antibiotics. Species that have acquired multidrug resistance and cause infections that are effectively untreatable present a serious threat to public health. The problem is broadly recognized and tackled at both the fundamental and applied levels. This paper summarizes current advances in understanding the molecular bases of the low permeability barrier of Gram-negative pathogens, which is the major obstacle in discovery and development of antibiotics effective against such pathogens. Gaps in knowledge and specific strategies to break this barrier and to achieve potent activities against difficult Gram-negative bacteria are also discussed.

show abstract

Section: Approaches To Bypass or Break The Permeability Barriermentioning

confidence: 99%

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similar composition of transporters is also found in Bacillus subtilis, carrying a least 265 transporter gene clusters, out of which 64 and 65 clusters encode ABC and MFS transporters, respectively (Table ). The resistance–nodulation–division (RND) superfamily of efflux transporters emerged as a major contributor to survival in adverse environments and clinical antibiotic resistance in bacteria. − In addition, members of SMR, MATE, and PACE families of efflux transporters all contribute to drug efflux, but the number of their gene clusters is low and their representatives are found only in a few of the analyzed bacterial genomes . In this section, we will focus on kinetic properties of the best-studied representatives of these families of transporters and their contributions to changes in the intracellular accumulation of small molecules (Table ).…”

Section: Active Transportersmentioning

confidence: 99%

The Whole Is Bigger than the Sum of Its Parts: Drug Transport in the Context of Two Membranes with Active Efflux

et al. 2021

Self Cite

View full text Add to dashboard Cite

Cell envelope plays a dual role in the life of bacteria by simultaneously protecting it from a hostile environment and facilitating access to beneficial molecules. At the heart of this ability lie the restrictive properties of the cellular membrane augmented by efflux transporters, which preclude intracellular penetration of most molecules except with the help of specialized uptake mediators. Recently, kinetic properties of the cell envelope came into focus driven on one hand by the urgent need in new antibiotics and, on the other hand, by experimental and theoretical advances in studies of transmembrane transport. A notable result from these studies is the development of a kinetic formalism that integrates the Michaelis–Menten behavior of individual transporters with transmembrane diffusion and offers a quantitative basis for the analysis of intracellular penetration of bioactive compounds. This review surveys key experimental and computational approaches to the investigation of transport by individual translocators and in whole cells, summarizes key findings from these studies and outlines implications for antibiotic discovery. Special emphasis is placed on Gram-negative bacteria, whose envelope contains two separate membranes. This feature sets these organisms apart from Gram-positive bacteria and eukaryotic cells by providing them with full benefits of the synergy between slow transmembrane diffusion and active efflux.

show abstract

“…Also in P. aeruginosa , elevated expression of MexXY is the major cause of aminoglycoside resistance in the absence of modifying enzymes (Poole and Srikumar, 2001 ). The unquestionably significant impact of multidrug efflux pumps on the effectiveness of antibiotics in clinical settings makes them attractive targets for inhibition (Lomovskaya et al, 2008a , b ). This review is focused on the mechanism of coupling drug transport reactions in the cytoplasmic and outer membranes.…”

Section: Transportersmentioning

confidence: 99%

Mechanism of coupling drug transport reactions located in two different membranes

et al. 2015

Self Cite

View full text Add to dashboard Cite

Gram- negative bacteria utilize a diverse array of multidrug transporters to pump toxic compounds out of the cell. Some transporters, together with periplasmic membrane fusion proteins (MFPs) and outer membrane channels, assemble trans-envelope complexes that expel multiple antibiotics across outer membranes of Gram-negative bacteria and into the external medium. Others further potentiate this efflux by pumping drugs across the inner membrane into the periplasm. Together these transporters create a powerful network of efflux that protects bacteria against a broad range of antimicrobial agents. This review is focused on the mechanism of coupling transport reactions located in two different membranes of Gram-negative bacteria. Using a combination of biochemical, genetic and biophysical approaches we have reconstructed the sequence of events leading to the assembly of trans-envelope drug efflux complexes and characterized the roles of periplasmic and outer membrane proteins in this process. Our recent data suggest a critical step in the activation of intermembrane efflux pumps, which is controlled by MFPs. We propose that the reaction cycles of transporters are tightly coupled to the assembly of the trans-envelope complexes. Transporters and MFPs exist in the inner membrane as dormant complexes. The activation of complexes is triggered by MFP binding to the outer membrane channel, which leads to a conformational change in the membrane proximal domain of MFP needed for stimulation of transporters. The activated MFP-transporter complex engages the outer membrane channel to expel substrates across the outer membrane. The recruitment of the channel is likely triggered by binding of effectors (substrates) to MFP or MFP-transporter complexes. This model together with recent structural and functional advances in the field of drug efflux provides a fairly detailed understanding of the mechanism of drug efflux across the two membranes.

show abstract

Bacterial Multidrug Transporters: Molecular and Clinical Aspects

Cited by 9 publications

References 168 publications

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

The Whole Is Bigger than the Sum of Its Parts: Drug Transport in the Context of Two Membranes with Active Efflux

Mechanism of coupling drug transport reactions located in two different membranes

Contact Info

Product

Resources

About