Blocking the Trigger: Inhibition of the Initiation of Bacterial Chromosome Replication as an Antimicrobial Strategy.

Julia E Grimwade,Alan C Leonard

doi:10.3390/antibiotics8030111

Julia E Grimwade, Alan C Leonard

Open Access

https://doi.org/10.3390/antibiotics8030111

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Journal: Antibiotics	Publication Date: Aug 6, 2019
Citations: 11	License type: CC BY 4.0

Affiliation: Florida Institute of Technology

Abstract

All bacterial cells must duplicate their genomes prior to dividing into two identical daughter cells. Chromosome replication is triggered when a nucleoprotein complex, termed the orisome, assembles, unwinds the duplex DNA, and recruits the proteins required to establish new replication forks. Obviously, the initiation of chromosome replication is essential to bacterial reproduction, but this process is not inhibited by any of the currently-used antimicrobial agents. Given the urgent need for new antibiotics to combat drug-resistant bacteria, it is logical to evaluate whether or not unexploited bacterial processes, such as orisome assembly, should be more closely examined for sources of novel drug targets. This review will summarize current knowledge about the proteins required for bacterial chromosome initiation, as well as how orisomes assemble and are regulated. Based upon this information, we discuss current efforts and potential strategies and challenges for inhibiting this initiation pharmacologically.

Highlights

Since the 1940s, antibiotics have become an integral part of global health care, and combined with advances in food handling, sewage treatment and other improvements in general hygiene, antibiotics have led to a dramatic decrease in mortality and morbidity caused by bacterial infections [1]
We alsofor discuss progress on ofidentifying new replication forks.inhibitors, In this review, we summarize current for knowledge orisomeinitiation
While the current lack of knowledge on diverse orisome assembly pathways could discourage the exploitation of this process for drug development, it should be noted that the major initiation proteins have been well-characterized in multiple bacterial types [99], and there are in vitro biochemical assays available that could allow an identification of compounds that target an individual protein or even a specific region of a protein

Summary

Introduction

Since the 1940s, antibiotics have become an integral part of global health care, and combined with advances in food handling, sewage treatment and other improvements in general hygiene, antibiotics have led to a dramatic decrease in mortality and morbidity caused by bacterial infections [1]. DnaA recruits DnaB and DnaC, binding to specific sequences in oriC and unwinding an A-T rich region termed the DNA Unwinding and helps position the helicase onto the newly-formed single strands of the unwound DUE [12]. In E. coli, this domain I-mediated oligomerization is required for bound DnaA to recruit and position a new DnaA monomer for binding to oriC [30] (see Section 3 below). In E. coli, one major reason that DnaA-ATP is required is to allow the initiator to fully occupy oriC [39], because a subset of the lower affinity recognition boxes in the origin preferentially bind this form [41,42]. It has been suggested that cryptic DnaA recognition sites may be a common feature of bacterial origins [53], but because binding studies are often required to identify them, it is not known how prevalent they are in the bacterial world

DnaB and DnaC

Orisome Assembly

A DnaA filament binds the single-stranded

Overview

In Vitro Screens Targeting DnaA and DnaB

Cell Based Screen for Inhibitors of Bacterial Replication Initiation