DnaG Primase—A Target for the Development of Novel Antibacterial Agents

Abstract

The bacterial primase—an essential component in the replisome—is a promising but underexploited target for novel antibiotic drugs. Bacterial primases have a markedly different structure than the human primase. Inhibition of primase activity is expected to selectively halt bacterial DNA replication. Evidence is growing that halting DNA replication has a bacteriocidal effect. Therefore, inhibitors of DNA primase could provide antibiotic agents. Compounds that inhibit bacterial DnaG primase have been developed using different approaches. In this paper, we provide an overview of the current literature on DNA primases as novel drug targets and the methods used to find their inhibitors. Although few inhibitors have been identified, there are still challenges to develop inhibitors that can efficiently halt DNA replication and may be applied in a clinical setting.

Dual Acting Small-Molecule Inhibitors Targeting Mycobacterial DNA Replication

“…The precise binding site of the three molecules (one containing 2H-chromene and two containing indole) within the T7 DNA primase was discovered by high field NMR spectroscopy 21 . T7 DNA primase shares high structural homology with bacterial DnaG primases and therefore it was used as a model target for the development of anti-DnaG small-molecule inhibitors 4 . On a DNA template containing the primase recognition site, DnaG catalyzes the synthesis of RNA primers ( Fig.…”

“…A method that combines NMR-fragment screening with an optimization using virtual screening (FBVS) was developed that selects inhibitors for DnaG-type DNA primase 20,21 . FBVS was found to be an effective method especially for challenging targets such as DNA primase 4,22 . This method yielded five small molecule inhibitors that target T7 DNA primase through a similar binding mechanism as shown by high field NMR 21 .…”

Prymazy prokariotyczne – budowa i funkcje

“…W dobie antybiotykooporności wielu szczepów bakteryjnych próbuje się znaleźć antybiotyki lub inne związki chemiczne, które wybiórczo hamowałyby aktywność prymaz bakteryjnych i prowadziły do zatrzymania replikacji DNA bakterii. Sposoby poszukiwania i różne podejścia do znalezienia skutecznych inhibitorów prymaz bakteryjnych zostały omówione w pracy przeglądowej [73]. Pomimo wielu prób jak do tej pory nie udało się znaleźć takiego związku, który znalazłby się w badaniach klinicznych, ale próby takie cały czas są podejmowane.…”

Dual‐Acting Small‐Molecule Inhibitors Targeting Mycobacterial DNA Replication

“…Therefore, DNA gyrase (Gyr), a type II topoisomerase, acts by creating transient double‐stranded DNA breaks to release the tension and ensures that the chromosome is always negatively supercoiled . Both DnaG primase and Gyr are essential for the viability of bacterial cells, whereas they have different structural and functional settings in human replisomes (Figure A), thereby providing attractive candidates for antibiotic targeting …”

“…We have previously reported a method that combines fragment‐based screening by NMR spectroscopy with in silico optimization steps to identify inhibitors for DnaG‐type DNA primase . Fragment‐based screening has advantages over commonly used high‐throughput screening for slow enzymes such as DNA primase, for which the readout of biochemical activity is extremely low . A subset of drug‐sized molecules that contain the same scaffold as the initial fragment molecules were selected from the ZINC database and docked into the crystal structure of T7 primase.…”