Host-dependent Induction of Transient Antibiotic Resistance: A Prelude to Treatment Failure.
Current antibiotic testing does not include the potential influence of host cell environment on microbial susceptibility and antibiotic resistance, hindering appropriate therapeutic intervention. We devised a strategy to identify the presence of host-pathogen interactions that alter antibiotic efficacy in vivo. Our findings revealed a bacterial mechanism that promotes antibiotic resistance in vivo at concentrations of drug that far exceed dosages determined by standardized antimicrobial testing. This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells. Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance. This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.
Dept. of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
Jessica Z
JZ
Kubicek-Sutherland
Dept. of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA ; Center for Nanomedicine, University of California, Santa Barbara, CA 93106, USA.
Douglas M
DM
Heithoff
Dept. of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
Selvi C
SC
Ersoy
Dept. of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
William R
WR
Shimp
University of Sydney, Faculty of Veterinary Science, Camden, NSW, Australia.
John K
JK
House
Dept. of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA ; Center for Nanomedicine, University of California, Santa Barbara, CA 93106, USA ; Sanford-Burnham Medical Research Institute, Cancer Research Center, La Jolla, CA 92037, USA.
Jamey D
JD
Marth
Sanford-Burnham Medical Research Institute, Cancer Research Center, La Jolla, CA 92037, USA.
Jeffrey W
JW
Smith
Dept. of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA ; Center for Nanomedicine, University of California, Santa Barbara, CA 93106, USA.
Michael J
MJ
Mahan
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy; D060833:Cellular Microenvironment / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004352:Drug Resistance, Microbial / Q000187:drug effects; D054884:Host-Pathogen Interactions / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D000067996:RAW 264.7 Cells; D017211:Treatment Failure
D000900:Anti-Bacterial Agents
Antibiotic resistance; Antibiotic susceptibility testing; Antibiotic-resistant mutants; Antimicrobial therapy; MIC testing; Multidrug-resistant pathogens; Salmonella