Antibacterial agents based on the cyclic D,L-alpha-peptide architecture.
The rapid emergence of bacterial infections that are resistant to many drugs underscores the need for new therapeutic agents. Here we report that six- and eight-residue cyclic d,l-alpha-peptides act preferentially on Gram-positive and/or Gram-negative bacterial membranes compared to mammalian cells, increase membrane permeability, collapse transmembrane ion potentials, and cause rapid cell death. The effectiveness of this class of materials as selective antibacterial agents is highlighted by the high efficacy observed against lethal methicillin-resistant Staphylococcus aureus infections in mice. Cyclic d,l-alpha-peptides are proteolytically stable, easy to synthesize, and can be derived from a potentially vast membrane-active sequence space. The unique abiotic structure of the cyclic peptides and their quick bactericidal action may also contribute to limit temporal acquirement of drug resistant bacteria. The low molecular weight d,l-alpha-peptides offer an attractive complement to the current arsenal of naturally derived antibiotics, and hold considerable potential in combating a variety of existing and emerging infectious diseases.
Fernandez-Lopez
S
S
Present address: Departamento de Química Orgánica, Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain.
Kim
H S
HS
Choi
E C
EC
Delgado
M
M
Granja
J R
JR
Khasanov
A
A
Kraehenbuehl
K
K
Long
G
G
Weinberger
D A
DA
Wilcoxen
K M
KM
Ghadiri
M R
MR
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D002462:Cell Membrane / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D015195:Drug Design; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010865:Pilot Projects; D013203:Staphylococcal Infections / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic