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.

1.7 A Ê with ARP 20 after 5% of the data had been set aside to calculate the free R-factor. Additional calculations were performed with the CCP4 suite of programs 21 . The model was re®ned with REFMAC 22 and water molecules were added with ARP. Model building was performed using the program O 23 . The ®nal model has been re®ned at 1.7 A Ê to an R-factor of 0.175 with an R free of 0.208 (Table 1). ATP and acyl-adenylate complexesCrystals of the apo complex were soaked for 24 h in a solution consisting of 1.7 M Li 2 SO 4 , 100 mM HEPES, pH 7.5, and 20 mM ATP. Diffraction data were collected at beamline X26C (99.7% complete, 6.3-fold redundancy, R sym = 12.9%), and the structure was solved using difference Fourier methods. The ATP-bound model has been re®ned at 2.9 A Ê to an R-factor of 0.203 (R free = 0.267). No water molecules were added owing to the limited resolution. Residues 167±188 and 241±248 appear to be disordered, including the zincbinding motifs and the previously missing surface loop of MoeB. In the apo complex, the polypeptide segments containing the zinc-binding motifs have higher average B-factors compared with the remainder of the molecule. At 2.9 A Ê the quality of the electron density maps for the ATP complex is reduced making it impossible to observe these more mobile regions. To obtain the acyl-adenylate complex, apo crystals were soaked for 24 h in a solution consisting of 1.7 M Li 2 SO 4 , 100 mM HEPES, pH 7.5, 20 mM ATP, and 20 mM MgSO 4 . Diffraction data were collected at beamline X26C (98.7% complete, 3.5-fold redundancy, R sym = 8.6%), and the structure was solved using difference Fourier methods. The acyl-adenylate model has been re®ned at 2.1 A Ê resolution to an R-factor of 0.188 (R free = 0.225) following the same protocol described for the apo complex. The residues in the zinc-binding motif of MoeB are present in the electron density maps in a conformation identical to that found in the apo complex, but residues 182±188 are again disordered.

No abstract