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.
journal_name
Proc Natl Acad Sci U S Aauthors
McGrath DM,Barbu EM,Driessen WH,Lasco TM,Tarrand JJ,Okhuysen PC,Kontoyiannis DP,Sidman RL,Pasqualini R,Arap Wdoi
10.1073/pnas.1221924110subject
Has Abstractpub_date
2013-02-26 00:00:00pages
3477-82issue
9eissn
0027-8424issn
1091-6490pii
1221924110journal_volume
110pub_type
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