title: Fusion with a cell wall binding domain renders autolysin LytM a potent anti-Staphylococcus aureus agent.
abstract: Despite intense efforts by the medical and pharmaceutical communities, Staphylococcus aureus continues to be a pervasive pathogen that causes a myriad of diseases and a high level of morbidity and mortality among infected patients. Thus, discovering or designing novel therapeutics able to kill both drug-resistant and drug-sensitive S. aureus remains a top priority. Bacteriolytic enzymes, mostly from phage, have shown great promise in preclinical studies, but little consideration has been given to cis-acting autolytic enzymes derived from the pathogen itself. Here, we use the S. aureus autolysin LytM as a proof of principal to demonstrate the antibacterial potential of endogenous peptidoglycan-degrading enzymes. While native LytM is only marginally bactericidal, fusion of LytM to the lysostaphin cell wall binding domain enhances its anti-staphylococcal activity approximately 540-fold, placing it on par with many phage lysins currently in preclinical development. The potential to therapeutically co-opt a pathogen's endogenous peptidoglycan recycling machinery opens the door to a previously untapped reservoir of antibacterial drug candidates.
authors: Program in Experimental and Molecular Medicine, Dartmouth, Hanover, NH 03755, USA.
authors: Daniel C
authors: DC
authors: Osipovitch
authors: Thayer School of Engineering, Dartmouth, Hanover, NH 03755, USA Program in Molecular and Cellular Biology, Dartmouth, Hanover, NH 03755, USA karl.e.griswold@dartmouth.edu.
authors: Karl E
authors: KE
authors: Griswold
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D001433:Bacteriolysis / Q000187:drug effects; D001435:Bacteriophages; D018441:Biofilms / Q000187:drug effects; D020134:Catalytic Domain; D002473:Cell Wall / Q000378:metabolism; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D008248:Lysostaphin / Q000737:chemistry / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D010457:Peptidoglycan / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000494:pharmacology; D016415:Sequence Alignment; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010457:Peptidoglycan; D011993:Recombinant Fusion Proteins; D010450:Endopeptidases; D008248:Lysostaphin; C120985:LytM protein, Staphylococcus aureus
keywords: M23 peptidase; MRSA; antimicrobial enzyme; lysin; pentaglycine; peptidoglycan hydrolysis