I’ve written how we often discovered antibiotics.  Simple.  By sampling mud, ponds, habitats where microbes thrive and try to find the one strain that inhibits the growth of other microbes.  Not a very efficient process- and one that provides less benefit now that we’ve discovered a slew of microbes.  We just can’t seem to find a new one that works, to bolster our arsenal against disease.

Which is why this new development is so exciting.  After all, it’s been about a half-century since a new antibiotic that kills Gram negative bacteria has received FDA approval.

Dr. Paul Hergenrother (U of Illinois- Urbana and  the Carl R Woese Institute for Genomic Biology, plus his grad student BS Drown) along with Drs. EN Parker, EJ Geddes, HY Lee, N Ismail, and GW Lau (all from Urbana) explained their new development in Nature Microbiology.  (Implementation of permeation rules leads to a FabI inhibitor with activity against Gram-negative pathogens)

What they developed is a web-based tool to discern which drugs can kill Gram negative microbes  The trick was determining which molecular features were necessary attributes for a potential antibiotic to transcend the Gram negative pathogen membranes.  That’s what eNTRyway does- discern if the chemical can cross the microbial barrier and then accumulate inside the microbe, so it will be killed.

BS Drown demonstrated that it can evaluate potential drug candidates- as well as suggest what changes could be made to existing drugs that are effective against Gram positive microbes to make them deadly when they encounter Gram negative ones.

Dr. Erica Parker, Hergenrother’s post-doc, used eNTRyway to determine what modifications a Gram positive drug would need to render it effective against the Gram negative bugs that cause mouse sepsis.  Parker used structure-activity relationships and x-Ray data to render Debio-1452 (heretofore effective only against Gram-positive bacteria) to accumulate in E. coli  and counter Gram negative pathogenic microbes.  (It required the addition of an amine group, a positively charged chemical, which she then termed Debio-1452-NH₃. And, took less than a few weeks- despite the previous work involving some 100 chemical relatives of the Debio-1452.  It turns out that it reduced the bacterial burden in mice and is effective when tested against Acinetobacter baumannii, Klebsiella pneumoniae, and E. coli. While the compound interferes with fatty acid synthesis in microbes, it has no such effect upon mammalian cells.)

Since that finding, the team has identified more than 5 dozen antibiotics that were useful against Gram positive microbes that can now be deployed against Gram negative pathogens.

Finally, a tool to develop chemicals to treat those antibiotic resistance Gram negative microbes!

This may turn the tide against antibiotic resistance.

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