
In the early 1900's Sir D'arcy Thompson lamented the absence of study of 'form in the naturalistic sciences' and attributed it to the lack of discourse between the physical sciences and biology. A century later we are only beginning to understand how physical principles determine cellular form, or morphology. In bacteria this is a very open question not only due to the tremendous variety of shapes but also to the dynamic feedback between the environment and these organisms; for instance, numerous bacteria change shape as they become pathogenic. Bacterial morphology is largely determined by peptidoglycan (PG), one of the largest macromolecules in the cell, whose synthetic enzymes are a main antibiotic target. PG is composed of repeating sugar monomers (glycans) connected by peptide linkages. The essential and well-conserved enzyme PBP2, working alongside other enzymes, is involved in peptidoglycan remodeling and is thought to be a key cross-linking enzyme. We applied biochemical and biophysical approaches to determine how the mechanical properties of the PG varied with shape, by substituting PBP2 from distantly related species into E. coli. We characterized these mutants based on morphological changes, cell-wall chemical components, ultrastructure mechanics and synthesis machinery kinetics. Based on this data, we have developed a biophysical model and demonstrated that the underlying cell-wall organization can tune cell shape in a systematic way, while maintaining the same chemical components. This fundamental understanding of the bacterial cell wall and its physical characteristics will allow us to better predict how it can be disrupted at a time in which antibiotic resistance is becoming an great challenge.

In the early 1900's Sir D'arcy Thompson lamented the absence of study of 'form in the naturalistic sciences' and attributed it to the lack of discourse between the physical sciences and biology. A century later we are only beginning to understand how physical principles determine cellular form, or morphology. In bacteria this is a very open question not only due to the tremendous variety of shapes but also to the dynamic feedback between the environment and these organisms; for instance, numerous bacteria change shape as they become pathogenic. Bacterial morphology is largely determined by peptidoglycan (PG), one of the largest macromolecules in the cell, whose synthetic enzymes are a main antibiotic target. PG is composed of repeating sugar monomers (glycans) connected by peptide linkages. The essential and well-conserved enzyme PBP2, working alongside other enzymes, is involved in peptidoglycan remodeling and is thought to be a key cross-linking enzyme. We applied biochemical and biophysical approaches to determine how the mechanical properties of the PG varied with shape, by substituting PBP2 from distantly related species into E. coli. We characterized these mutants based on morphological changes, cell-wall chemical components, ultrastructure mechanics and synthesis machinery kinetics. Based on this data, we have developed a biophysical model and demonstrated that the underlying cell-wall organization can tune cell shape in a systematic way, while maintaining the same chemical components. This fundamental understanding of the bacterial cell wall and its physical characteristics will allow us to better predict how it can be disrupted at a time in which antibiotic resistance is becoming an great challenge.