title: Pentobra: A Potent Antibiotic with Multiple Layers of Selective Antimicrobial Mechanisms against Propionibacterium Acnes.
abstract: Although antibiotics are a common treatment for acne, the difficulties inherent to effective antimicrobial penetration in sebum and selective antimicrobial action in the skin are compounded by increasing resistance of Propionibacterium acnes clinical isolates. To address these problems, we engineered Pentobra, a peptide-aminoglycoside molecule that has multiple mechanisms of antibacterial action and investigated whether it can be a potential candidate for the treatment of acne. Pentobra combines the potent ribosomal activity of aminoglycosides with the bacteria-selective membrane-permeabilizing abilities of antimicrobial peptides. Pentobra demonstrated potent and selective killing of P. acnes but not against human skin cells in vitro. In direct comparison, Pentobra demonstrated bactericidal activity and drastically outperformed free tobramycin (by 5-7 logs) against multiple P. acnes clinical strains. Moreover, electron microscopic studies showed that Pentobra had robust membrane activity, as treatment with Pentobra killed P. acnes cells and caused leakage of intracellular contents. Pentobra may also have potential anti-inflammatory effects as demonstrated by suppression of some P. acnes-induced chemokines. Importantly, the killing activity was maintained in sebaceous environments as Pentobra was bactericidal against clinical isolates in comedones extracts isolated from human donors. Our work demonstrates that equipping aminoglycosides with selective membrane activity is a viable approach for developing antibiotics against P. acnes that are effective in cutaneous environments.
authors: Department of Bioengineering, University of California, Los Angeles, California, USA; Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA.
authors: Nathan W
authors: NW
authors: Schmidt
authors: Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors: George W
authors: GW
authors: Agak
authors: Department of Bioengineering, University of California, Los Angeles, California, USA; Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA.
authors: Stephanie
authors: S
authors: Deshayes
authors: Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors: Yang
authors: Y
authors: Yu
authors: Department of Bioengineering, University of California, Los Angeles, California, USA; Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA.
authors: Alyssa
authors: A
authors: Blacker
authors: Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors: Jackson
authors: J
authors: Champer
authors: Department of Bioengineering, University of California, Los Angeles, California, USA; Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA.
authors: Wujing
authors: W
authors: Xian
authors: Department of Bioengineering, University of California, Los Angeles, California, USA; California NanoSystems Institute, University of California, Los Angeles, California, USA.
authors: Andrea M
authors: AM
authors: Kasko
authors: Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA; California NanoSystems Institute, University of California, Los Angeles, California, USA; Department of Dermatology, Greater Los Angeles Healthcare System Veterans Affairs, Los Angeles, California, USA.
authors: Jenny
authors: J
authors: Kim
authors: Department of Bioengineering, University of California, Los Angeles, California, USA; Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA; California NanoSystems Institute, University of California, Los Angeles, California, USA. Electronic address: gclwong@seas.ucla.edu.
authors: Gerard C L
authors: GCL
authors: Wong
mesh_terms: D000152:Acne Vulgaris / Q000188:drug therapy; D000617:Aminoglycosides / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D002462:Cell Membrane / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008826:Microbial Sensitivity Tests; D008854:Microscopy, Electron; D009000:Monocytes / Q000187:drug effects; D010455:Peptides / Q000737:chemistry*; D011425:Propionibacterium acnes / Q000187:drug effects*; D012867:Skin / Q000187:drug effects / Q000382:microbiology; D013045:Species Specificity; D013234:Stem Cells; D014031:Tobramycin / Q000737:chemistry
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D016207:Cytokines; C000599818:Pentobra; D010455:Peptides; D014031:Tobramycin