6W9T

Crystal structure of Neisseria meningitidis ClpP protease complex with small molecule activator ACP1-06

Summary for 6W9T

• Entry DOI: 10.2210/pdb6w9t/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit, POTASSIUM ION, N-{2-[(2-chlorophenyl)sulfanyl]ethyl}-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}propanamide, ... (4 entities in total)
• Functional Keywords: serine protease, proteostasis, activator, complex, antibacterial drugs, hydrolase
• Biological source: Neisseria meningitidis
• Total number of polymer chains: 7
• Total formula weight: 155687.88

Authors

Mabanglo, M.F.,Houry, W.A. (deposition date: 2020-03-23, release date: 2020-12-09, Last modification date: 2023-10-18)

Primary citation

Binepal, G.,Mabanglo, M.F.,Goodreid, J.D.,Leung, E.,Barghash, M.M.,Wong, K.S.,Lin, F.,Cossette, M.,Bansagi, J.,Song, B.,Balasco Serrao, V.H.,Pai, E.F.,Batey, R.A.,Gray-Owen, S.D.,Houry, W.A.
Development of Antibiotics That Dysregulate the Neisserial ClpP Protease.
Acs Infect Dis., 6:3224-3236, 2020

PubMed Abstract: Evolving antimicrobial resistance has motivated the search for novel targets and alternative therapies. Caseinolytic protease (ClpP) has emerged as an enticing new target since its function is conserved and essential for bacterial fitness, and because its inhibition or dysregulation leads to bacterial cell death. ClpP protease function controls global protein homeostasis and is, therefore, crucial for the maintenance of the bacterial proteome during growth and infection. Previously, acyldepsipeptides (ADEPs) were discovered to dysregulate ClpP, leading to bactericidal activity against both actively growing and dormant Gram-positive pathogens. Unfortunately, these compounds had very low efficacy against Gram-negative bacteria. Hence, we sought to develop non-ADEP ClpP-targeting compounds with activity against Gram-negative species and called these activators of self-compartmentalizing proteases (ACPs). These ACPs bind and dysregulate ClpP in a manner similar to ADEPs, effectively digesting bacteria from the inside out. Here, we performed further ACP derivatization and testing to improve the efficacy and breadth of coverage of selected ACPs against Gram-negative bacteria. We observed that a diverse collection of and clinical isolates were exquisitely sensitive to these ACP analogues. Furthermore, based on the ACP-ClpP cocrystal structure solved here, we demonstrate that ACPs could be designed to be species specific. This validates the feasibility of drug-based targeting of ClpP in Gram-negative bacteria.

PubMed: 33237740
DOI: 10.1021/acsinfecdis.0c00599

Experimental method

X-RAY DIFFRACTION (1.64 Å)