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Targeting Resistant Bacterial Pathogens with Next Generation Antifolates
Author(s) -
Wright Dennis
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.939.12
Subject(s) - dihydrofolate reductase , biology , microbiology and biotechnology , klebsiella pneumoniae , trimethoprim , escherichia coli , antibiotics , enterobacteriaceae , drug resistance , antifolate , gene , genetics , antimetabolite , chemotherapy
Bactrim (trimethoprim‐sulfamethoxazole) remains one of the most important oral antibiotics for treatment of both Gram‐positive and Gram‐negative infections, most notably in the community setting. Resistance to trimethoprim (TMP) is on the rise and can occur either through mutations to the chromosomal copy of the target, dihydrofolate reductase (DHFR), or by the acquisition of additional plasmid‐encoded DHFRs that are natively resistant to TMP. Over the past decade, we have focused on the development of next generation propargyl‐linked antifolates (PLAs) that maintain activity against many of the important pathogenic bacterial DHFR enzymes while expanding coverage to include both mutant and naturally TMP‐insensitive DHFR enzymes that give rise to TMP resistance. While analyzing contemporary TMP‐resistant clinical isolates of methicillin‐resistant and sensitive Staphylococcus aureus , we discovered two mobile resistance elements, dfrG and dfrK (Cell Chem. Biol., In Press). This is the first identification of these resistance mechanisms in United States clinical strains. These resistant organisms were isolated from a variety of infection sites, show clonal diversity and display differing susceptibility patterns to common antibiotics. Excitingly, several of the PLAs showed significant activity against these highly resistant bacteria. This design has also been extended to the major resistant elements found in Gram‐negative Enterobacteriaceae, notably Escherichia coli and Klebsiella pneumoniae . For example, a prevalent gene ( dfr A1) coding for an insensitive dihydrofolate reductase (DHFR) confers 190‐ or 1000‐fold resistance to trimethoprim for K. pneumoniae and E. coli , respectively. Members of the PLA class of antifolates are active against both the wild‐type and DfrA1 DHFR proteins and we have recently reported two high resolution crystal structures of DfrA1 bound to potent PLAs. Structure‐based drug design against these variable, resistant DHFRs is ongoing to develop superior inhibitors with potent antibiotic activity. Support or Funding Information This work has been supported by the National Institutes of Health through grants AI104841 and AI111957.Crystal Structure of a PLA Bound to Dihydrofolate Reductase