title: Novel mechanism of antibiotic resistance originating in vancomycin-intermediate Staphylococcus aureus.
abstract: As an aggressive pathogen, Staphylococcus aureus poses a significant public health threat and is becoming increasingly resistant to currently available antibiotics, including vancomycin, the drug of last resort for gram-positive bacterial infections. S. aureus with intermediate levels of resistance to vancomycin (vancomycin-intermediate S. aureus [VISA]) was first identified in 1996. The resistance mechanism of VISA, however, has not yet been clarified. We have previously shown that cell wall thickening is a common feature of VISA, and we have proposed that a thickened cell wall is a phenotypic determinant for vancomycin resistance in VISA (L. Cui, X. Ma, K. Sato, et al., J. Clin. Microbiol. 41:5-14, 2003). Here we show the occurrence of an anomalous diffusion of vancomycin through the VISA cell wall, which is caused by clogging of the cell wall with vancomycin itself. A series of experiments demonstrates that the thickened cell wall of VISA could protect ongoing peptidoglycan biosynthesis in the cytoplasmic membrane from vancomycin inhibition, allowing the cells to continue producing nascent cell wall peptidoglycan and thus making the cells resistant to vancomycin. We conclude that the cooperative effect of the clogging and cell wall thickening enables VISA to prevent vancomycin from reaching its true target in the cytoplasmic membrane, exhibiting a new class of antibiotic resistance in gram-positive pathogens.
authors.affiliation: Department of Bacteriology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. longzhu@med.juntendo.ac.jp
authors.forename: Longzhu
authors.initials: L
authors.lastname: Cui
authors.forename: Akira
authors.initials: A
authors.lastname: Iwamoto
authors.forename: Jian-Qi
authors.initials: JQ
authors.lastname: Lian
authors.forename: Hui-min
authors.initials: HM
authors.lastname: Neoh
authors.forename: Toshiki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Yataro
authors.initials: Y
authors.lastname: Horikawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hiramatsu
mesh_terms: D002473:Cell Wall / Q000648:ultrastructure; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008433:Mathematics; D008954:Models, Biological; D010457:Peptidoglycan / Q000096:biosynthesis; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D017211:Treatment Failure; D014640:Vancomycin / Q000378:metabolism; D020713:Vancomycin Resistance
chemical_list: D010457:Peptidoglycan; D014640:Vancomycin; D005947:Glucose