Heads of Laboratories
Many symptoms of bacterial disease can be traced to molecular events at the surface of the invading bacteria. A bacterium’s cell wall is also the target of antibiotics designed to interrupt its replication. But with antibiotic resistance, bacteria acquire or modify genetic determinants to remodel the replication machinery so that it withstands disruption. Thus, several issues of microbiology, medicine, chemotherapy and infectious disease converge in the structure and molecular biology of the bacterial cell wall.
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 human disease. Dr. Tomasz’s work focuses on Streptococcus pneumoniae and Staphylococcus aureus, two major human pathogens that frequently cause community- and hospital-acquired disease. Multidrug-resistant clones of these two pathogens have acquired global spread.
Cell walls may be envisioned as vast networks of covalent bonds organized into macromolecular sheets with the shape and size of the entire bacterial cell. How these “super” molecules are reproduced with precision in every cell division as often as every 20 minutes is one of the most intriguing questions of microbial cell biology. 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 suicidal process — a kind of programmed cell death — in the bacteria that leads to the killing and dissolution of the cells. A special mechanism named “antibiotic tolerance,” which enables bacterial cells to evade this intriguing suicidal pathway, was discovered in the Tomasz lab in the mid-1970s.
Tolerant bacteria survive the antibiotic but are still inhibited by it. Antibiotic-resistant bacteria can overcome even the inhibitory effects of these agents. In the mid-1990s the Tomasz lab was the first to demonstrate that penicillin resistance in S. pneumoniae involves the reengineering of the structure of a family of proteins, named penicillin-binding proteins (PBPs), so as to reduce their affinity for the antibiotic. The genetic program for this reengineering involves the import of blocks of foreign DNA by pneumococci, which then use them to alter genetic determinants of its PBPs and change their affinity for the antibiotic. In the late 1960s, the Tomasz lab identified a critical component of this DNA uptake mechanism: pneumococci secrete a polypeptide that induces the expression of proteins to allow foreign DNA to pass through its walls. This hormone-like substance was the first of numerous “quorum-sensing” factors that have since been identified in many microbial phenomena. Pneumococci with the reengineered PBPs are not only resistant to penicillin but also show an altered chemical structure of their cell walls.
All methicillin-resistant S. aureus strains carry a foreign gene called mecA, which is the critical component of the resistance mechanism. Recent data from the Tomasz lab strongly suggest that the evolutionary source of mecA is a cell wall synthetic gene ubiquitous in all isolates of the animal commensal species S. sciuri.
Using whole genome sequencing, the Tomasz lab was recently able to identify specific mutations that accompanied the evolution of antibiotic resistance in an S. aureus strain recovered from the bloodstream of a patient undergoing extensive chemotherapy by vancomycin.
To understand how bacteria cause disease, the Tomasz lab is 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.
The Tomasz lab is also using molecular fingerprinting to track the spread of antibiotic-resistant clones of staphylococci and pneumococci. Many of these investigations are done in collaboration with other labs in Europe and South America.
Dr. Tomasz, a native of Hungary, earned his Ph.D. in biochemistry from Columbia University in 1963 and joined Rollin D. Hotchkiss’s Rockefeller laboratory as a postdoc. He became assistant professor in 1964, associate professor in 1967 and professor and head of laboratory in 1973.
In 1998 Dr. Tomasz was named to an endowed chair in infectious diseases honoring the late Greek microbiologist Plutarch Papamarkou. In 1987 he received the Selman A. Waksman Award in Microbiology. In 1982 he received the first Hoechst-Roussel Award in antimicrobial chemotherapy from the American Society for Microbiology.
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