Heads of Laboratories
Dr. Plutarch Papamarkou Professor
Laboratory of Microbiology and Infectious Diseases
The cell walls of pathogenic bacteria are the site of molecular events responsible for many symptoms of bacterial disease, as well as the target for antibiotics. Focusing on Streptococcus pneumoniae and Staphylococcus aureus, Dr. Tomasz studies how bacteria cause disease and resist antibiotics, often through mechanisms involving their cell walls.
Dr. Tomasz’s laboratory uses biochemistry and molecular genetics in combination with firsthand medical knowledge to study three basic problems: how the bacterial cell wall is assembled and replicated; how bacteria respond to antibiotic treatment and ultimately gain resistance; and how bacteria cause disease. Dr. Tomasz’s work focuses on Streptococcus pneumoniae and Staphylococcus aureus, two major human pathogens with multidrug-resistant clones that have spread globally.
A significant conceptual contribution of the laboratory came in the late 1960s, with the discovery that pneumococci secrete a polypeptide that allows foreign DNA to pass through cell walls. This has been cited as the first evidence that bacteria “talk” to one another, a concept later called “quorum sensing.”
Cell walls may be envisioned as vast networks of covalent bonds organized into macromolecular sheets. How these “super” molecules are reproduced with precision in every cell division is an intriguing question. Using conditional mutants of key cell wall biosynthetic genes, the Tomasz lab aims to identify genetic determinants and protein catalysts involved with this morphogenetic process.
Antibiotic resistance is a growing problem. Treatment of S. pneumoniae and S. aureus with penicillins or glycopeptide antibiotics triggers a kind of programmed cell death for these cells. A mechanism named “antibiotic tolerance,” which enables bacterial cells to evade this suicidal pathway, was discovered in the Tomasz lab in the mid-1970s.
Tolerant bacteria survive the antibiotic but are still inhibited by it, while antibiotic-resistant bacteria can overcome even the inhibitory effects of these agents. In the mid-1990s, building off its much earlier discovery of the first quorum sensing factor, the Tomasz lab was the first to demonstrate that penicillin resistance in S. pneumoniae involves the reengineering of penicillin-binding proteins (PBPs) using blocks of foreign DNA that reduce PBPs’ affinity for the antibiotic. Pneumococci with the reengineered PBPs are not only resistant to penicillin but show an altered chemical structure of their cell walls.
A number of other projects in the Tomasz lab have focused on cell walls’ role in disease and antibiotic resistance. Recent data from the Tomasz lab on mecA, a foreign gene critical to methicillin resistance in S. aureus, suggests mecA originated as a cell wall synthetic gene ubiquitous in the animal commensal species Staphylococcus sciuri. The Tomasz lab is also investigating alterations in the chemical structure of the cell wall that can have a profound impact on bacterial virulence. For instance, mutants of S. pneumoniae that produce a cell wall lacking phosphoryl choline residues suffer a profound loss in virulence.
Other work includes using whole genome sequencing to identify specific mutations that accompanied the evolution of antibiotic resistance in an S. aureus strain from a patient undergoing extensive chemotherapy by vancomycin. The Tomasz lab is also tracking the spread of antibiotic-resistant clones of staphylococci and pneumococci, often in collaboration with labs in Europe and South America.
Ph.D. in biochemistry, 1963
The Rockefeller University, 1963–1964
Assistant Professor, 1964–1967
Associate Professor, 1967–1973
The Rockefeller University
ASM Hoechst-Roussel Award, 1982
Selman A. Waksman Award, 1987
Gardete, S. and Tomasz, A. Mechanisms of vancomycin resistance in Staphylococcus aureus. J. Clin. Invest. 124, 2836–2840 (2014).
Dordel, J. et al. Novel determinants of antibiotic resistance: identification of mutated loci in highly methicillin-resistant subpopulations of methicillin-resistant Staphyloccocus aureus. MBio 5, e01000 (2014).
Mwangi, M.M. et al. Whole-genome sequencing reveals a link between β-lactam resistance and synthetases of the alarmone
(p)ppGpp in Staphylococcus aureus. Microb. Drug Resist. 19, 153–159 (2013).
Kim, C. et al. The mechanism of heterogeneous β-lactam resistance in MRSA: key role of the stringent stress response. PLoS One 8, e82814 (2013).
Frazão, N. et al. Virulence potential and genome-wide characterization of drug resistant Streptococcus pneumoniae clones selected in vivo by the 7-valent pneumococcal conjugate vaccine. PLoS One 8, e74867 (2013).