Infections caused by Gram-negative bacterial pathogens are on the rise in hospital and non-hospital settings. Indeed 4 of the 6 ?ESKAPE? pathogens ? recently highlighted as responsible for the majority of hospital infections and being exceedingly difficult to treat ? are Gram-negatives. The development of new antibiotics is complicated by the fact that Gram-negative bacteria have a highly impenetrable membrane that confers significant intrinsic resistance to antibacterial agents. Without advances, we will soon face a crisis situation whereby our current antibiotics can no longer effectively treat these infections. Although it is clear that novel antibiotics for Gram-negative infections are desperately needed, there has been minimal progress in this regard, and it has been over 50 years since a new class of drugs have been introduced for Gram-negative pathogens. Why is this? A chief reason is that no rules or guidelines have been developed that enable the accurate prediction of compound accumulation in Gram-negatives, thus it has been difficult to convert Gram-positive-only drugs into broad-spectrum agents, and impossible to create large collections of compounds that are biased for Gram-negative accumulation. We have been working to define the physicochemical features of small molecules that allow them to accumulate in E. coli. In important preliminary results we have assessed >180 diverse compounds for their ability to accumulate in E. coli; using a sophisticated computation analysis of the data, we have begun to discern the physicochemical traits that govern compound accumulation in E. coli, and we have used these guidelines to convert a Gram-positive-only antibiotic into one that also has activity against many Gram-negative pathogens. We now propose to gain a further understanding of compound accumulation in E. coli (especially with respect to porin penetration and pump-mediated efflux), and to extend these guidelines to other Gram-negative pathogens. We will also use the guidelines to convert important FDA-approved antibiotics that are currently only effective against Gram-positive bacteria into derivatives that are also active against Gram-negative organisms. Finally, we will use our guidelines to design and construct a collection of thousands of compounds all of which are heavily biased for accumulation in Gram-negative bacteria. Significant outputs of this work include a fundamental understanding of the types of compounds that accumulate in Gram-negative bacteria, and actionable guidelines to be used to discover novel antibacterials.
The arsenal of antibiotics for treating Gram-negative bacterial infections is sorely in need of enhancement, but discovery of effective drugs is complicated by the fact that it is notoriously difficult for drug candidates to penetrate and accumulate inside Gram-negative bacteria. We have utilized a novel and systematic approach to develop guidelines governing physicochemical properties that influence compound accumulation in E. coli. We now propose to extend this approach to other Gram-negative organism, to use these guidelines to convert certain Gram- positive-only drugs to broad spectrum agents, and to identify novel classes of compounds active against the most problematic Gram-negative pathogens.
| Drown, Bryon S; Hergenrother, Paul J (2018) Going on offense against the gram-negative defense. Proc Natl Acad Sci U S A 115:6530-6532 |
