Mechanism of action and initial evaluation of a membrane active all-D-enantiomer antimicrobial peptidomimetic.

Abstract:

:Development of therapy against infections caused by antibiotic-resistant pathogens is a major unmet need in contemporary medicine. In previous work, our group chemically modified an antimicrobial peptidomimetic motif for targeted applications against cancer and obesity. Here, we show that the modified motif per se is resistant to proteolytic degradation and is a candidate antiinfective agent. We also show that the susceptibility of microorganisms to the drug is independent of bacterial growth phase. Moreover, this peptidomimetic selectively interferes with the integrity and function of the microbial surface lipid bilayer, data indicative that bacterial death results from membrane disruption followed by dissipation of membrane potential. Finally, we demonstrate two potential translational applications: use against biofilms and synergy with antibiotics in use. In summary, we introduce the mechanism of action and the initial evaluation of a prototype drug and a platform for the development of D-enantiomer antimicrobial peptidomimetics that target bacterial membranes of certain gram-negative problem pathogens with promising translational applications.

authors

McGrath DM,Barbu EM,Driessen WH,Lasco TM,Tarrand JJ,Okhuysen PC,Kontoyiannis DP,Sidman RL,Pasqualini R,Arap W

doi

10.1073/pnas.1221924110

subject

Has Abstract

pub_date

2013-02-26 00:00:00

pages

3477-82

issue

9

eissn

0027-8424

issn

1091-6490

pii

1221924110

journal_volume

110

pub_type

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