title: The bactericidal activity of β-lactam antibiotics is increased by metabolizable sugar species.
abstract: Here, the influence of metabolizable sugars on the susceptibility of Escherichia coli to β-lactam antibiotics was investigated. Notably, monitoring growth and survival of mono- and combination-treated planktonic cultures showed a 1000- to 10 000-fold higher antibacterial efficacy of carbenicillin and cefuroxime in the presence of certain sugars, whereas other metabolites had no effect on β-lactam sensitivity. This effect was unrelated to changes in growth rate. Light microscopy and flow cytometry profiling revealed that bacterial filaments, formed due to β-lactam-mediated inhibition of cell division, rapidly appeared upon β-lactam mono-treatment and remained stable for up to 18 h. The presence of metabolizable sugars in the medium did not change the rate of filamentation, but led to lysis of the filaments within a few hours. No lysis occurred in E. coli mutants unable to metabolize the sugars, thus establishing sugar metabolism as an important factor influencing the bactericidal outcome of β-lactam treatment. Interestingly, the effect of sugar on β-lactam susceptibility was suppressed in a strain unable to synthesize the nutrient stress alarmone (p)ppGpp. Here, to the best of our knowledge, we demonstrate for the first time a specific and significant increase in β-lactam sensitivity due to sugar metabolism in planktonic, exponentially growing bacteria, unrelated to general nutrient availability or growth rate. Understanding the mechanisms underlying the nutritional influences on antibiotic sensitivity is likely to reveal new proteins or pathways that can be targeted by novel compounds, adding to the list of pharmacodynamic adjuvants that increase the efficiency and lifespan of conventional antibiotics.
authors.affiliation: Costerton Biofilm Center, Department of Immunology and Microbiology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Thorsing
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bentin
authors.affiliation: Costerton Biofilm Center, Department of Immunology and Microbiology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark.|Singapore Center on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 639798, Singapore.
authors.forename: Michael
authors.initials: M
authors.lastname: Givskov
authors.affiliation: Costerton Biofilm Center, Department of Immunology and Microbiology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark.
authors.forename: Tim
authors.initials: T
authors.lastname: Tolker-Nielsen
authors.affiliation: Costerton Biofilm Center, Department of Immunology and Microbiology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Goltermann
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001433:Bacteriolysis / Q000187:drug effects; D002228:Carbenicillin / Q000494:pharmacology; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000494:pharmacology*; D002444:Cefuroxime / Q000494:pharmacology; D004357:Drug Synergism; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D005434:Flow Cytometry; D050296:Microbial Viability / Q000187:drug effects*; D008853:Microscopy; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D002241:Carbohydrates; D047090:beta-Lactams; D002228:Carbenicillin; D002444:Cefuroxime