Discovering the Genetic and Evolutionary Basis of Bacterial Antibiotic Resistance

Tomasz, Alexander

In the 1940s and 1950s the first truly effective antibiotics came into use, including penicillin and methicillin. These drugs transformed medicine, but releasing them into the environment in enormous quantities unleashed a backlash from the microbial world. Powerful selective pressure from antibiotics forced bacterial pathogens into a kind of accelerated evolution: mutants with altered antibiotic resistant target proteins emerged and resistance genes became "mobilized" to spread through many pathogenic species. That is how antibiotic-resistant pathogens such as penicillin-resistant pneumococci and methicillin-resistant S. aureus (MRSA) have evolved. Less than five decades after the introduction of penicillin, the rapid emergence and spread of multi-resistant pathogens had begun to pose serious problems to the therapy of infectious diseases worldwide; this was the conclusion of national and international experts that convened in a workshop organized by Alexander Tomasz at The Rockefeller University in 1994. 

Tomasz has led the field in investigating bacterial evolution as it occurs in the real life, in vivo, environment of pathogenic microbes. In the 1960s he discovered what later became known as the first "quorum sensing" factor, a kind of bacterial hormone excreted by individual cells that makes an entire population of bacteria receptive for taking up DNA molecules carrying resistance factors. For example, pneumococcus—one of the most dangerous pathogens producing pneumonia-becomes resistant to penicillin by "borrowing" pieces of foreign DNA from other bacteria. Tomasz found that this enables the pneumococcus to remodel its penicillin target proteins, the so-called penicillin binding proteins, so that they can withstand the assault of the antibiotic molecule. Analysis of this phenomenon by Tomasz and colleagues led to the discovery of a novel survival strategy of bacteria, named antibiotic tolerance. They later found that a single foreign genetic determinant, also encoding a low affinity penicillin binding protein, is the basis of the wide-spectrum antibiotic resistance in methicillin-resistant staphylococci (MRSA). These MRSA strains have become the most frequent agents of serious hospital and community acquired infections in our era Tomasz's group tentatively identified the actual evolutionary source of the genetic determinant conferring methicillin resistance—the so-called mecA gene—in another staphylococcus species that inhabits the skin flora of many wild and domestic animals.

Some of the most powerful antimicrobial agents target the mechanism by which bacteria synthesize a cell wall, leading to unique structural changes in these molecules. The characterization of these changes in the bacterial surface has become one of the major contributions of the Tomasz lab to microbial cell biology.

Once human pathogens such as Staphylococcus aureus or Streptococcus pneumoniae manage to equip themselves with antibiotic resistance genes, they can then produce antibiotic-resistant clones that can be identified by molecular fingerprinting techniques. The Tomasz lab pioneered in launching the first international network to study the molecular epidemiology of drug resistant staphylococci, pneumococci and enterococci in collaboration with the Laboratory of Molecular Genetics of the Instituto de Tecnologia Química e Biológica (ITQB) in Portugal.  This initiative was the first to demonstrate widespread occurrence of multi-resistant pneumococcal and MRSA clones in hospitals in New York City as well as hospitals and Day Care Centers in twenty different countries in Europe, South America, and Asia.

With the arrival of the era of full genome sequencing the collection of thousands of well-characterized bacterial isolates has become a critical resource for tracing the evolution of antibiotic resistant clones of staphylococci during intercontinental spread- as it was reported in a recent collaborative study with the The Wellcome Trust Sanger Institute.  Full genome sequencing was also used by the Tomasz lab to identify genetic steps that accompanied the evolution of antibiotic resistance in vivo in a patient undergoing chemotherapy with the antibiotic vancomycin.

Alexander Tomasz, a native of Hungary, received the PhD in Biochemistry from Columbia University (1963). He then joined the laboratory of Rollin Hotchkiss at Rockefeller as a postdoctoral fellow. At Rockefeller, Hotchkiss and René Dubos were pioneers in launching the antibiotic era, and both had worked under Oswald Avery, who identified DNA as the "transforming factor" that could change a harmless bacterium into a pathogenic one. Tomasz became assistant professor in 1964, associate professor in 1967, and professor and head of laboratory in 1973. In 1998 he was named to an endowed chair in infectious diseases honoring the late Greek microbiologist Plutarch Papamarkou. His achievements have been recognized with the first Hoechst-Roussel Award in antimicrobial chemotherapy from the American Society for Microbiology (1982) and the Selman A. Waksman Award in Microbiology (1987).

Selected Publications

Tomasz A. Multiple-antibiotic-resistant pathogenic bacteria. A report on the Rockefeller University workshop. N Engl J Med, 1994, 330: 1247-1251

Tomasz A. Control of the competent state in pneumococcus by a hormone-like cell product: an example for a new type of regulatory mechanism in bacteria. Nature, 1965, 208: 155-159

Bassler BL and Losick R. Bacterially speaking. Cell, 2006, 125:237-46.

Zighelboim S and Tomasz A. Penicillin-binding proteins of the multiply antibiotic-resistant South African strains of Streptococcus pneumoniae. Antimicrob Agents Chemother, 1980, 17: 434-442

Tomasz A, Albino A, and Zanati E. Multiple antibiotic resistance in a bacterium with suppressed autolytic system. Nature, 1970, 227: 138-140

Hartman B and Tomasz A. Altered penicillin-binding proteins in methicillin-resistant strains of Staphylococcus aureus. Antimicrob Agents Chemother, 1981, 19: 726-735

de Lencastre H, Oliveira DC, and Tomasz A. Antibiotic resistant Staphylococcus aureus: a paradigm of adaptive power. Curr Opin Microbiol, 2007, 10: 1-8

Couto I, de Lencastre H, Severina E, Kloos W, Webster JA, Hubner RJ, Santos Sanches I, and Tomasz A. Ubiquitous presence of a mecA homologue in natural isolates of Staphylococcus sciuri. Microb Drug Resist, 1996, 2: 377-391

Antignac A and Tomasz A. Reconstruction of the phenotype of methicillin resistant Staphylococcus aureus (MRSA) by replacement of the staphylococcal cassette chromosome mec (SCCmec) with a plasmid-borne copy of S. sciuri pbpD gene. Antimicrob Agents Chemother, 2009, 53: 435-441

Severin A, Tabei K, Tenover F, Chung M, Clarke N, and Tomasz A. High level oxacillin and vancomycin resistance and altered cell wall composition in Staphylococcus aureus carrying both the staphylococcal mecA gene and the enterococcal vanA gene complex. J Biol Chem, 2004, 279: 3398-3407

Oliveira DC, Tomasz A, and de Lencastre H. Secrets of success of a human pathogen: molecular evolution of pandemic clones of methicillin-resistant Staphylococcus aureus. Lancet Infect Dis, 2002, 2: 180-189

Roberts RB, de Lencastre A, Eisner W, Severina EP, Shopsin B, Kreiswirth BN, Tomasz A, and the MRSA Collaborative Study Group. Molecular epidemiology of methicillin-resistant Staphylococcus aureus in twelve New York hospitals. J Infect Dis, 1998, 178: 164-171

Muñoz R, Coffey TJ, Daniels M, Dowson CG, Laible G, Casal J, Hakenbeck R, Jacobs M, Musser JM, Spratt BG, and Tomasz A. Intercontinental spread of a multiresistant clone of serotype 23F Streptococcus pneumoniae. J Infect Dis, 1991, 164: 302-306

Harris, S, Feil EJ, Holden MTG, Quail MA, Nickerson EK, Chantratita N, Gardete, Tavares A, Day N, Lindsay J, Edgeworth, de Lencastre, Parkhill J, Peacock SJ, and Bentley, SD. 2009. Evolution of MRSA during hospital transmission and intercontinental spread. Science. In press

Mwangi MM, Wu SW, Yanjiao Z, Sieradzki K, de Lencastre H, Richardson P, Bruce D, Rubin E, Myers E, Siggia ED, and Tomasz A. Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing. Proc Natl Acad Sci USA, 2007, 104: 9451-9456

Further Reading

Moberg CL and Cohn ZA, eds. Launching The Antibiotic Era. Personal Accounts of the Discovery and Use of the First Antibiotics. New York: The Rockefeller University Press, 1990