Structural studies of antibiotics targeting bacterial cell-wall biosynthesis

Nicoleta J. Economou

doi:10.17918/00000697

Gram-positive bacteria (e.g. streptococci, enterococci) are a main source of fatal nosocomial and community-acquired infections. With the use of antibiotics to treat these infections, bacterial pathogens have developed antibiotic resistance. Our long-term goal is to obtain structural information for the rational design of new antimicrobials that will circumvent the existing bacterial resistance mechanisms. Bacteria acquire resistance towards some antibiotics rapidly, whereas for others this process takes decades. Antibiotics that do not trigger rapid resistance mechanisms typically target nonenzymatic bacterial components, for instance those essential for cell wall biosynthesis. We determined the interactions of bacterial components with commonly-used antimicrobials, including glycopeptide antibiotics and bacitracin. The size and nature of these antibiotics can potentially hinder their crystallographic study, either during crystallization or structure determination. For glycopeptide antibiotics, we developed a carrier protein strategy that allowed the facile crystallization and structure determination of a variety of antibiotics in complex with their ligands. Among others, we determined the first-ever structure for dalbavancin, as well as the first liganded structures of teicoplanin and a monoliganded ristocetin dimer. All glycopeptides form five signature hydrogen bonds with their ligand, as well as van der Waals interactions. We illustrated the importance of these interactions and identified the associated glycopeptide groups. Additionally, we characterized those structural properties of glycopeptide antibiotics that affect their cooperativity, an attribute that enhances their antimicrobial potencies, and provided insights into how some glycopeptides have enhanced half-lives. In addition to our work on glycopeptide antibiotics, we also determined the first crystal structure for bacitracin in complex with its target. We overcame crystallographic obstacles with this complex using a truncated surrogate of the ligand and a zinc ion. This allowed us to successfully crystallize and obtain an initial model of bacitracin bound to its target. From this initial structure, we identified the key amino acids that are important for bacitracin-ligand recognition and provided structural insights into bacitracin's mechanism of action. The information provided by the study of glycopeptides and bacitracin can assist in the rational design of new-generation drugs targeting antibiotic-resistant bacteria.

Structural studies of antibiotics targeting bacterial cell-wall biosynthesis

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Structural studies of antibiotics targeting bacterial cell-wall biosynthesis

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