Understanding the mechanical response of bacterial cell walls and cell membranes against antimicrobial agents[HBNI Th179]

Abstract

Bacteria are single celled, prokaryotic micro-organisms that were one of the first life forms to appear on earth and have since emerged as one of the most successful organisms as well, populating habitats as diverse as hot springs, human gut, even radioactive waste [1]. They have formed complex and varied associations with humans, which in several instances has turned out to be beneficial for both. However, bacteria are also responsible for causing several serious diseases in human beings, including tuberculosis, diptheria, typhus, leprosy [2]. A crucial step in managing such bacterial infections has been the development of antibiotics, which fight bacterial infections either by killing bacteria or by slowing its growth, usually by impeding crucial cellular functions like cell wall synthesis and protein synthesis in the cell. However, several strains of bacteria have started displaying an alarming rise in resistance to antibiotic treatment. This has rendered several commonly used antibiotics largely ineffective. Indeed, strains of the bacteria Escherichia coli have even developed resistance to colistin and carbapenem, two antibiotics of \last resort" [3]. It has been estimated that by 2050, infections from multi-drug resistant pathogens will cause higher mortality than cancer [4], which gives an insight into the graveness of this public health crisis. This necessitates the exploration and design of newer antibacterial agents. For this, an important pathway is to utilize biophysical methods to unravel the design principles of the bacterial cell and to model the action of antimicrobial agents on them, thus enabling us to effectively design and test the efficacy of new age antibacterials. This thesis is divided into two parts. In the first part, we study the design features of the cell wall of bacteria, which is primarily composed of the peptidoglycan (PG) network, a mesh of relatively long and stiff glycan chains, cross-linked intermittently by flexible peptides. We explore the molecular scale architecture of the PG mesh and its role in enhancing the toughness or the resistance to crack propagation, of the cell wall, utilizing theoretical methods. We also investigate the effect of variability in the elastic properties of the PG mesh on its bulk mechanical response, by studying an appropriately modelled spring system using theoretical methods and simulations. In the second part of the thesis, we study the conformational landscape, aggregation dynamics and interactions with model bacterial membrane of biomimetic antimicrobial polymers (AMPolys), utilizing detailed atomistic molecular dynamics simulations. We specifically examine the role played by neutral polar groups in influencing the aggregation dynamics of such polymers in solution phase and study their membrane-interactions in depth. Further, we also investigate the conformational landscape of AMPolys that have anionic functional groups as constituents, with particular focus on probing the formation of salt bridges and their role in determining the conformational dynamics of such polymers.