Multiscale Models of Antibiotic Cellbots
Antibiotic resistance has raised serious concerns over the last two decades. A significant need exists to develop technologies to control colonization and transmission of resistant bacteria, such as enterococci, as these microorganisms are becoming an escalating threat to mankind. Over the last three decades, enterococcal strains have evolved to resist almost all antibiotics, including vancomycin, long considered an antibiotic of last resort for many infections. Patients with VRE (Vancomycin Resistant Enterococci) infection have increased mortality, morbidity, length of hospital stay, and hospital costs, in comparison to uninfected groups.
The Kaznessis group is studying bacteriocins that target VRE. Bacteriocins are defined as ribosomally synthesized peptides produced by bacteria that inhibit the growth of other closely related bacteria. Peptide-membrane interactions are important for function. With molecular simulations, the researchers will explain experimental observations of activity and determine the sequence and structural features of these peptides that underlie function. They have developed models that quantify the molecular interactions between antimicrobial peptides and cell membranes, the loss of membrane structural integrity, the collapse of the transmembrane potential, cell lysis, and death. With these models, a clear timeline of biophysical steps that underlie AMP function can be generated. Consequently, peptide sequence and structure may be correlated to antimicrobial activity. The researchers use NAMD with the CHARMM force field. The details of the simulation protocol vary slightly in each case, but the following key features are common to all: a 2 femtosecond time step for all calculations, along with SHAKE restraints on all bonds involving hydrogen; the CHARMM c36 force field along with the TIP3P water model; the use of particle mesh Ewald (PME) summation for the treatment of long-range electrostatic forces; a potential cutoff of 12Å, smoothly decreased to zero between 10 and 12 Å.
A bibliography of this group’s publications is attached. A Research Spotlight about an article that appeared in PNAS appeared on the MSI website in January 2014.
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