Targeting the Achilles’ Heel of Bacteria: Different Mechanisms To Break Down the Peptidoglycan Cell Wall during Bacterial Warfare

Abstract

Bacteria commonly live in dense polymicrobial communities and compete for scarce resources. Consequently, they employ a diverse array of mechanisms to harm, inhibit and kill their competitors. The cell wall is essential for bacterial survival by providing mechanical strength to resist osmotic stress. Because peptidoglycan is the major component of the cell wall and its synthesis is a complex multi-step pathway that requires the coordinate action of several enzymes, it provides a target for rival bacteria, which have developed a large arsenal of antibacterial molecules to attack the peptidoglycan of competitors. These molecules include antibiotics, bacteriocins and contact-dependent effectors that are either secreted into the medium or directly translocated into a target cell. In this review, we summarize the diversity of these molecules and highlight distinct mechanisms to disrupt the peptidoglycan, giving special attention to molecules that are known or have the potential to be used during interbacterial competitions.

Higher-order effects, continuous species interactions, and trait evolution shape microbial spatial dynamics

“…Modeled in this fashion, phenotypic changes could plausibly represent the outcome of a diverse set of microbial mutational processes, given that the details of such processes affecting antagonistic microbial interactions are still in their infancy (for details see refs. 10 , 11 , and 76 to 84 ). We emphasize that we do not model mutations at a genotype level because HGT, which plays a major role in trait evolution in microbes, especially bacteriocins ( 10 , 11 , 77 ), is not easily amenable to such modeling.…”

“…There is no underlying genotypic space, and our phenotypic microbial space abstracts away genotypic changes into expressed phenotypic traits. Doing this in a meaningful way is a very difficult problem, and this is especially true for bacterial toxin-based antagonisms in which the basic nature of the interactions remains at a preliminary level of research and discovery (11,(76)(77)(78)(79)(80)(81)(82)(83)(84). At fixed-interval time steps, the state of the microbial space is updated synchronously in four stages.…”

“…This approach, which is mathematically simple compared to alternative representations of trait evolution ( SI Appendix , Supplemental Methods and Fig. S6 ), is a reasonable starting point because the true nature of the relationship between antibiotic production and vulnerability across microbial species is very much unknown ( 10 , 11 , 76 – 84 ).…”

Demonstration of N , N -Dimethyldithiocarbamate as a Copper-Dependent Antibiotic against Multiple Upper Respiratory Tract Pathogens

“…Microbial resistance to traditional antibiotics is an existential risk and a central focus of global health. Innovation tends to focus on well-studied, canonical targets, such as the cell wall (β-lactams) or translation (aminoglycosides) ( 1 – 3 ). This strong and near-global selection pressure is evident by examples of clinical resistance only years after introduction.…”

Direct and indirect interactions promote complexes of the lipoprotein LbcA, the CtpA protease and its substrates, and other cell wall proteins in Pseudomonas aeruginosa

“…Many critical virulence factors are assembled or exported through the cell envelope, including the type III secretion system (T3SS) and the polysaccharide alginate, which play important roles in acute and chronic infections, respectively (2,3). The peptidoglycan cell wall is a layer of the cell envelope that helps maintain bacterial cell integrity, has to be remodeled during growth and virulence factor assembly/export, and is one of the most important targets for antibiotics (4)(5)(6). Therefore, a comprehensive understanding of proteins involved in cell wall assembly, remodeling and associated functions has obvious significance.…”