title: Investigations to the Antibacterial Mechanism of Action of Kendomycin.
abstract: OBJECTIVE
  The emergence of bacteria that are resistant to many currently used drugs emphasizes the need to discover and develop new antibiotics that are effective against such multi-resistant strains. Kendomycin is a novel polyketide that has a unique quinone methide ansa structure and various biological properties. This compound exhibits strong antibacterial activity against Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Despite the promise of kendomycinin in several therapeutic areas, its mode of action has yet to be identified.
  
  
  METHODS
  In this study, we used a multidisciplinary approach to gain insight into the antibacterial mechanism of this compound.
  
  
  RESULTS
  The antibacterial activity of kendomycin appears to be bacteriostatic rather than bactericidal. Kendomycin inhibited the growth of the MRSA strain COL at a low concentration (MIC of 5 μg/mL). Proteomic analysis and gene transcription profiling of kendomycin-treated cells indicated that this compound affected the regulation of numerous proteins and genes involved in central metabolic pathways, such as the tricarboxylic acid (TCA) cycle (SdhA) and gluconeogenesis (PckA and GapB), cell wall biosynthesis and cell division (FtsA, FtsZ, and MurAA), capsule production (Cap5A and Cap5C), bacterial programmed cell death (LrgA and CidA), the cellular stress response (ClpB, ClpC, ClpP, GroEL, DnaK, and GrpE), and oxidative stress (AhpC and KatA). Electron microscopy revealed that kendomycin strongly affected septum formation during cell division. Most kendomycin-treated cells displayed incomplete septa with abnormal morphology.
  
  
  CONCLUSIONS
  Kendomycin might directly or indirectly affect the cell division machinery, protein stability, and programmed cell death in S. aureus. Additional studies are still needed to obtain deeper insight into the mode of action of kendomycin.
authors.affiliation: Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.|Faculty of Science, Zoology Department, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Elnakady
authors.affiliation: Institute of Medical Microbiology and Hygiene, Saarland University, Homburg, Germany.
authors.forename: Indranil
authors.initials: I
authors.lastname: Chatterjee
authors.affiliation: Institute of Medical Microbiology and Hygiene, Saarland University, Homburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bischoff
authors.affiliation: Department of Medical Microbiology, Helmholtz Center for Infection Research, Braunschweig, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Rohde
authors.affiliation: Department of Medical Microbiology, Bonn University, Bonn, Germany.
authors.forename: Michaele
authors.initials: M
authors.lastname: Josten
authors.affiliation: Department of Medical Microbiology, Bonn University, Bonn, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sahl
authors.affiliation: Institute of Medical Microbiology and Hygiene, Saarland University, Homburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D000085:Acetates / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015180:Electrophoresis, Gel, Two-Dimensional; D020869:Gene Expression Profiling; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D008826:Microbial Sensitivity Tests; D020543:Proteome / Q000187:drug effects / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000085:Acetates; D000900:Anti-Bacterial Agents; D020543:Proteome; C485395:kendomycin; D017828:Rifabutin