GmPcides: Componds that disarm antibiotic resistance in multiple gram-positive pathogens

PROJECT SUMMARY/ABSTRACT:
Hospital-Acquired Infections (HAI) have become a health care crisis and are a leading cause of death.
Further the hospital setting harbors a reservoir of lethal multidrug resistant (MDR) organisms, two million
patients suffer from HAI annually, resulting in 100,000 deaths and up to $4.5 billion in additional health care
expense. Thus, there is a global health emergency due to the growing prevalence of infections caused by MDR
HAI pathogens.
To combat these pathogens, we introduce GmPcides, a novel family of ring-fused 2-pyridone compounds
that are bactericidal against a broad spectrum of Gram-positive species, including all seven Gram-positive
species identified by the CDC as among the most significant antibiotic-resistant threats. These bacteria include
Clostridioides difficile, vancomycin-resistant Enterococci (VRE), methicillin-resistant Staphylococcus aureus
(MRSA), drug-resistant Streptococcus pneumoniae (S. pneumoniae), erythromycin-resistant Group A
Streptococcus (S. pyogenes) and clindamycin-resistant Group B Streptococcus (S. agalactiae). Significantly,
GmPcides are active against non-dividing bacteria and at sub-lethal doses, can disarm resistance, to re-
sensitize MDR microbes to antibiotic treatment, both in vitro and in vivo in a murine model of HAI infection to
standard-of-care antibiotics targeting multiple orthogonal processes. GmPcides have no effect on Gram-
negative viability or significant toxicity to host tissues. Our group developed GmPcides by combining the
talents of synthetic chemist Dr. Fredrik Almqvist with microbiologists Drs. Michael Caparon and Scott Hultgren
who propose to take advantage of their understanding of HAI pathogenesis and their unprecedented ability to
manipulate the substituent diversity of the 2-pyridone scaffold to address issues essential for the translation of
GmPcides, including: i) optimization of activity, stability and solubility through structure-activity relationship
(SAR) and structure-property relationship (SPR) studies; ii) Identification of the GmPcide target(s) using a
systems-level chemical-genetic approach and the comprehensive genetic resources available for the model
Gram-positive organism Bacillus subtilis; iii) optimization of activity against HAI bacteria growing in biofilm
communities; and iv) assessment of the in vivo efficacy of improved GmPcides in murine models of HAI
urinary tract and soft tissue infection. These experiments described here will lead to the identification of critical
druggable target(s) highly conserved among Gram-positive HAI pathogens and will lead to the development of
new antibiotic-sparing and antibiotic-disarming therapies to combat the challenge of MDR HAI Gram-positive
pathogens.
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Grant Number: 5U19AI157797-05
NIH Institute/Center: NIH
Principal Investigator: Michael Caparon