Finding the missing links in the bacterial cell cycle

Introduction

The bacterial pathogen Staphylococcus aureus is currently the second most common cause of death associated with antibiotic-resistant infections. The most useful antibiotics in clinical use have multiple targets, as compounds against single proteins rapidly succumb to the capacity of bacteria to develop resistance.

Innovative Antibiotic Discovery

To think innovatively about antibiotic discovery, we need to consider:

• Individual cellular processes
• How these processes are interconnected and coordinated

This approach will help us devise methods to strike bacterial cells simultaneously in multiple pathways.

Bacterial Cell Cycle

The bacterial cell cycle consists of a series of coordinated events required for bacterial growth. During this cycle, cells:

1. Duplicate their mass
2. Undergo chromosome replication and segregation
3. Assemble the division machinery
4. Perform cytokinesis
5. Separate to generate two new daughter cells

Unregulated cell cycle progression may have lethal consequences for the cell. Therefore, bacteria have evolved various mechanisms for the precise spatiotemporal control of main cell cycle events.

Checkpoints and Mechanisms

Some important checkpoints have been studied, particularly the link between chromosome replication/segregation and septum synthesis, to avoid DNA breaks. However, the mechanisms for coordination of other cell cycle events are still unknown. Key questions include:

• What triggers the initiation of peptidoglycan synthesis, the target of beta-lactam antibiotics, after the assembly of the division machinery?
• How does the cell coordinate the synthesis of the membrane and peptidoglycan, the two major cell surface components, during cell division?
• What prevents premature septum splitting, which would expose an immature cell surface devoid of virulence factors, leading to pathogen elimination by the innate immune system of an infected host?

Project Aim

The aim of this project is to find the missing links between major cell cycle events while also developing assays useful for antibiotic discovery.