Mechanism of action and initial evaluation of a membrane active all-D-enantiomer antimicrobial peptidomimetic.
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.
Department of Genitourinary Medical Oncology, David H. Koch Center, Houston, TX 77030, USA.
Danielle M
DM
McGrath
E Magda
EM
Barbu
Wouter H P
WH
Driessen
Todd M
TM
Lasco
Jeffrey J
JJ
Tarrand
Pablo C
PC
Okhuysen
Dimitrios P
DP
Kontoyiannis
Richard L
RL
Sidman
Renata
R
Pasqualini
Wadih
W
Arap
D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D018441:Biofilms / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004352:Drug Resistance, Microbial / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007700:Kinetics; D008051:Lipid Bilayers / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D013237:Stereoisomerism; D013997:Time Factors
D000890:Anti-Infective Agents; D008051:Lipid Bilayers; D057786:Peptidomimetics; D010743:Phospholipids