Bacterial survival depends on a robust, intricately assembled cell wall, constructed by a dynamic network of enzymes that coordinate peptidoglycan biosynthesis. While beta-lactam antibiotics target one key enzyme in this process, the full molecular machinery remains underexplored. Our lab investigates this multi-enzyme cell wall "nanomachine" using high-resolution structural and biophysical approaches to reveal how its components interact and function. By mapping this complex system, we aim to uncover new vulnerabilities that can be exploited for novel antibiotics, expanding the therapeutic landscape in the face of rising drug resistance. In the past, our projects have involved mapping out key proteins in conventional cell wall synthesis, including Pbp1b, Pbp2, and UppP.


AmpG, the inner membrane permease responsible for cell wall recycling. This mechanism has a dual use of also triggering resistance mechanisms in the presence of beta lactam antibiotics. Sverak et al. (2024), Nature Communications.

One key transporter in this intricate system is AmpG, the protein responsible for transporting peptidoglycan fragments from the periplasm to cytoplasm in Gram-negative bacteria. Under normal conditions, this protein helps maintain bacterial fitness by recycling energetically costly components of the cell wall. However, under antibiotic stress, unprocessed peptidoglycan fragments accumulate and once transported to the cytoplasm, bind to the regulatory protein AmpR. This induces production of the beta-lactamase AmpC, a key antibiotic resistance mechanism in P. aeruginosa. Our lab published the first atomic resolution structure of AmpG, providing key insights for a new potential target against Gram-negative bacteria.

Beyond the enzymes involved in the peptidoglycan cell wall, we are also interested in several additional aspects of cell surface biogenesis, including the synthesis of wall teichoic acid (WTA). Anionic teichoic acid polymers, along with peptidoglycan, are essential components of the Gram-positive cell wall. Despite being present in roughly equal amounts, very little is known about its synthesis in comparison to peptidoglycan. WTA is anchored to muramic acid of peptidoglycan. Along with lipoteichoic acid (anchored to the membrane) it is proposed to function in virulence, biofilm formation, autolysin regulation, physical protection, cation homeostasis and potential phosphate reservoir. Our lab has characterized a series of proteins involved in this process, including TarL, TarS, TarM, LcpA, and most recently, TarGH. These structures provide much needed detail to this pathway, creating opportunities at every step for new targets against this essential process in Gram-positive bacteria.

Selected Publications