Antibiotic resistance: multidrug efflux proteins, a common transport mechanism?

Langton, Kate; Henderson, Peter J. F.; Herbert, Richard B.

doi:10.1039/b413734p

Cited by 41 publications

(41 citation statements)

References 72 publications

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“…A mutation resulting in overexpression of a multidrug efflux pump leads to resistance to a wide variety of structurally unrelated antimicrobials [2]. Multidrug resistance proteins (MDRs) or multidrug efflux pumps are widespread in bacteria [7]. They are grouped into five families based on their mechanisms and primary sequence homologies.…”

Section: Efflux Pumpsmentioning

confidence: 99%

Antimicrobial resistance in bacteria

Bockstael

Aerschot

2009

Open Medicine

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AbstractThe development of antimicrobial resistance by bacteria is inevitable and is considered as a major problem in the treatment of bacterial infections in the hospital and in the community. Despite efforts to develop new therapeutics that interact with new targets, resistance has been reported even to these agents. In this review, an overview is given of the many therapeutic possibilities that exist for treatment of bacterial infections and how bacteria become resistant to these therapeutics.

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Section: Efflux Pumpsmentioning

confidence: 99%

Antimicrobial resistance in bacteria

Bockstael

Aerschot

2009

Open Medicine

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“…Conventional classes of antimicrobial agents kill bacterial organisms or inhibit their growth by targeting specific metabolic pathways or microbial structures. A resulting undesired property of these antibiotics is the selection of resistance-conferring mutations and/or acquisition of other resistance determinants during antimicrobial therapy (11)(12)(13). This is a major obstacle to treatment efficacy in a number of infections, such as those associated with cystic fibrosis (CF) (14,15), the use of medical implants (16,17), intensive care (18), and other nosocomial infections (19).…”

mentioning

confidence: 99%

Rational Design of Engineered Cationic Antimicrobial Peptides Consisting Exclusively of Arginine and Tryptophan, and Their Activity against Multidrug-Resistant Pathogens

Deslouches

Steckbeck

Craigo

et al. 2013

Antimicrob Agents Chemother

142

139

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cThe emergence of multidrug-resistant (MDR) pathogens underscores the need for new antimicrobial agents to overcome the resistance mechanisms of these organisms. Cationic antimicrobial peptides (CAPs) provide a potential source of new antimicrobial therapeutics. We previously characterized a lytic base unit (LBU) series of engineered CAPs (eCAPs) of 12 to 48 residues demonstrating maximum antibacterial selectivity at 24 residues. Further, Trp substitution in LBU sequences increased activity against both P. aeruginosa and S. aureus under challenging conditions (e.g., saline, divalent cations, and serum). Based on these findings, we hypothesized that the optimal length and, therefore, the cost for maximum eCAP activity under physiologically relevant conditions could be significantly reduced using only Arg and Trp arranged to form idealized amphipathic helices. Hence, we developed a novel peptide series, composed only of Arg and Trp, in a sequence predicted and verified by circular dichroism to fold into optimized amphipathic helices. The most effective antimicrobial activity was achieved at 12 residues in length (WR12) against a panel of both Gram-negative and Gram-positive clinical isolates, including extensively drug-resistant strains, in saline and broth culture and at various pH values. The results demonstrate that the rational design of CAPs can lead to a significant reduction in the length and the number of amino acids used in peptide design to achieve optimal potency and selectivity against specific pathogens.

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“…The yield and purity of protein may well be increased by further optimization of conditions, especially for detergent extraction of protein from the membrane. Our typical yields from 30-to 100-L fermentations (29) conducted approximately monthly are sufficient to maintain three-dimensional crystallization trials for x-ray crystallography and nuclear magnetic resonance (NMR) studies (50,51).…”

Section: Conclusion and Discussionmentioning

confidence: 99%