Antibiotic testing and screening system
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Publication Number
US-10760110-B2
Publication Date
2020-09-01
Expiration Date
Abstract
The present invention provides a platform technology for testing, screening, selecting and evaluating antibiotics by using genetically engineered strains with identified, individual or combined, resistance mechanisms, prepared from fully susceptible clinical isolates. This antibiotic testing and screening system of the present invention can efficiently and effectively evaluate antibiotics against specified resistance mechanisms in vitro and in vivo, and is suitable on the novel antibiotic development in against multidrug-resistant bacteria.
Core Innovation
The invention provides a method for screening for an antimicrobial agent using a wild-type (WT) susceptible bacterial strain and a genetic engineering (GE) resistant bacterial strain. The GE resistant bacterial strain is generated from the WT susceptible bacterial strain by genetic engineering to confer drug resistance based on one or more drug resistant mechanisms selected from decreased antibiotic permeability by loss of outer membrane proteins, pump out antibiotics by overexpression of efflux pumps, eliminates or reduces binding of antibiotic by modification of antibiotic target or acquirement of antibiotic-resistant target, and inactivation of antibiotic by enzymatic cleavage or modification.
In the method, the WT susceptible bacterial strain is cultured in the presence of the test agent and a MIC value is measured. Separately, the GE resistant bacterial strain is cultured in the presence of the test agent and a MIC value is measured for the GE resistant bacterial strain. A comparison result is obtained by comparing the MIC value against the WT susceptible bacterial strain with the MIC value against the GE resistant bacterial strain.
The invention determines whether the test agent is a potentially effective antimicrobial agent against the drug resistance based on the comparison result. An insignificant difference between the MIC value of the test agent against the GE resistant bacterial strain and the MIC value of the test agent against the WT susceptible bacterial strain indicates that the test agent is a potentially effective antimicrobial agent against the drug resistance.
Claims Coverage
The patent includes one independent method claim and dependent claims that refine the genetic engineering resistance mechanisms, applicable bacterial species/strains, and the quantitative definition of insignificant difference.
Mic-based screening using WT vs GE resistant strains
A method for screening for an antimicrobial agent comprising providing a wild-type (WT) susceptible bacterial strain; providing a genetic engineering (GE) resistant bacterial strain generated from the WT susceptible bacterial strain via genetic engineering to confer a drug resistance; culturing the WT susceptible bacterial strain in the presence of a test agent and measuring a minimum inhibitory concentration (MIC) value; culturing the GE resistant bacterial strain in the presence of the test agent and measuring a MIC value; comparing the MIC value against the WT susceptible bacterial strain with the MIC value against the GE resistant bacterial strain to obtain a comparison result.
Potential effectiveness defined by insignificant MIC difference
Determining whether the test agent is a potentially effective antimicrobial agent against the drug resistance based on the comparison result, wherein an insignificant difference between the MIC value against the GE resistant bacterial strain and the MIC value against the WT susceptible bacterial strain indicates that the test agent is a potentially effective antimicrobial agent against the drug resistance.
Engineering drug resistance by selected mechanisms
Conferring a drug resistance in the GE resistant bacterial strain by genetic engineering based on one or more drug resistant mechanisms selected from decreased antibiotic permeability by loss of outer membrane proteins, overexpression of efflux pumps, modification of antibiotic target or acquirement of antibiotic-resistant target, and enzymatic cleavage or modification of antibiotic.
Overall, the claim set covers a MIC-comparison screening approach that evaluates antimicrobial agents by culturing a WT susceptible strain and a genetically engineered resistant derivative carrying specified resistance mechanisms, then determining potentially effective status when the MIC difference is insignificant.
Stated Advantages
Allows determination of whether a test agent is a potentially effective antimicrobial agent against the drug resistance based on an insignificant difference between MIC values of the GE resistant and WT susceptible strains.
Documented Applications
Screening for antimicrobial agents against drug resistance using genetically engineered resistant bacterial strains and comparing MIC values between GE resistant and WT susceptible bacterial strains.
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