Description:
Technology: MUSC inventors identified a new chemical scaffold (N-aroylanthranilic acids and derivatives) as inhibitors of various class B penicillin-binding proteins (PBPs). The novel molecules showed high potency of PBP inhibition. Antimicrobial assays against antibiotic-resistant gonorrhea strain FA19 and H041 showed significant growth inhibition at the µM level.
Figure 1: Activity data for compound 1. A. PBP inhibition was determined in a purified protein assay in which a given PBP was preincubated with 100 μM compound, followed by addition of 1 μM Bocillin-FL. Data are presented as a fraction of DMSO control. B. Antimicrobial activity was determined in a disc diffusion assay against susceptible reference gonococcal strain FA19 and multi-drug resistant H041 at 10 μg per disc. Data for a ceftriaxone control disc (CRO) are shown.
Data showed compound 1 inhibited PBP activity when incubated with truncated PBP2 and PBP3 (Figure 1A). The compound also inhibited growth rate significantly in antibiotic-resistant strains FA19 and H041 (Figure 1B). To further optimize potency, compound 1 derivatives were generated. Ten compound 1 derivatives were found to inhibit PBP activity at 10 µM, and the compounds also reduced the bacterial growth at 10 µg level (Figure 2).
Figure 2: Inhibition data for representative compound 1 derivatives against tPBP2H041 at 10 μM. Values were determined in a purified protein assay in which tPBP2H041 was preincubated with 10 μM compound, followed by addition of 1 μM Bocillin-FL. Data are presented as a fraction of activity of the DMSO control. Disc diffusion data for potent representative compound 1 derivatives against N. gonorrhoeae FA19 and H041. Compounds were tested against susceptible reference gonococcal strain FA19 and multi-drug resistant H041 at 10 μg per disc. Data for a ceftriaxone control disc (CRO) are shown.
In summary, the novel compounds showed a promising inhibitory effect on PBP activity and the growth of antibiotic-resistant gonorrhea, which could also translate to other pathogenic bacteria.
Overview: β-lactams (penicillins, cephalosporins, and carbapenems) are the most widely used antibiotics. At the molecular level, β-lactams target the transpeptidase activity of penicillin-binding proteins (PBPs) that are involved in bacterial cell-wall biosynthesis, resulting in bacterial death. However, several gram-negative bacteria have acquired resistance to the antibiotics due to the production of a specific B-lactams hydrolase, presence of low-affinity PBPS, and active expulsion of B-lactams via efflux pumps. There is an unmet need to develop new antibiotics to overcome the treatment of bacterial infection.
Applications: Antibiotics, Bacterial infection
Advantages: The novel class of antibiotics inhibits the gram-negative bacterial that have resistance to the current antibiotics.
Key Words: Antibiotics, antibiotic-resistant Neisseria gonorrhoeae, bacterial infection
Inventors: Patrick Woster, Christopher Davies, Jonathan Turner, Joy Kirkpatrick
Patent Status: Provisional filed on 6/15/2020
MUSC-FRD Technology ID: P20148