Research on Antibiotic Resistance in Bacteria
Bacterial infections have become a very serious issue of public health as a result of resistance developed or acquired toward almost all the antibiotics that are in use today. It has become clear that bacteria have the potential to develop resistance fairly easy toward an antibiotic due to the high mutagenesis rate of its genome and the genetic cross-talking among bacteria.
Our focus is to understand the signaling mechanisms involved in induction of antibiotic resistance factors in pathogenic bacteria and especially in methicillin–resistant Staphylococcus aureus. This strain has acquired resistance to almost all the clinically used antibiotics including vancomycin, an antibiotic of the last resort.
The phenomenon of bacterial and viral resistance has raised the questions: Can we inhibit bacterial or viral infections without giving rise to resistance. To put it differently: Is there a resistance-proof biological target? If this is possible, then what biological properties a resistance-proof target should have? Our group is investigating the answers to these questions and the solutions to these problems.
Research on Human immunodeficiency (HIV) viral infection
Two main strategies have been pursued in inhibiting the HIV infection:
- developing vaccines and
- designing small molecules, organic- or peptide–based drugs that inhibit different stages of virus life-cycle.
However, development of resistance has compromised the success in these efforts i.e. virus evolves to acquire a resistance when exposed to a neutralizing antibody or a drug.
Our group is interested in looking closely at the fusion process of HIV virus with the host cells, and proteins involved in this step. The envelope glycoprotein complex is of special interest. Chemical and biological tools will be used to study the protein-protein interactions involved in the formation of this complex and biophysical methods will be used to quantitatively analyze these interactions.
Thomas V, Golemi-Kotra D., Kim, C., Vakulenko S. B., Mobashery S. and Shoichet B. The effect of S130G mutant in substrate and inhibitor spectrum of TEM-1 ß-lactamase. Biochemistry, 2005, 44, 9330-9338.
Golemi-Kotra D., Meroueh S. O., Kim C., Vakulenko S. B. Bulychev A., Stemmer A., Stemmer T. L. and Mobashery S. The importance of a critical protonation state and the fate of the catalytic steps in class A ß-lactamases and penicillin binding proteins. J. Biol. Chem. 2004, 279, 34665-73.
Golemi-Kotra D., Mahaffy R., Footer M., Holtzman J., Pollard T., Theriot J. and Schepartz A. High affinity, paralog-specific recognition of the Mena EVH1 domain by a miniature protein ligand. J. Am. Chem. Soc. 2004, 126, 4-5.
Golemi-Kotra D., Young Cha J., Meroueh S. O., Vakulenko S. B. and Mobashery S. Resistance to ß-lactam antibiotics and its mediation by the sensor domain of the transmembrane sensor-transducer signaling pathway in Staphylococcus aureus. J. Biol. Chem. 2003, 278, 18419-18425.
Meroueh S.O., Roblin P., Golemi D., Maveyraud L., Vakulenko S. B. Zhang Y., Samama J. P., Mobashery S. Molecular dynamics at the root of expansion of function in the M68L inhibitor-resistant TEM ß-lactamase from Escherichia coli. J. Am. Chem. Soc. 2002, 24, 9422-30.
Maveyraud L., Golemi D., Mobashery S., Samama J. P. High-resolution X ray structure of an acyl-enzyme species for the class D OXA-10 ß-lactamase. J. Am. Chem. Soc. 2002, 124, 9422-9430.
Vakulenko S. and Golemi D. Mutant TEM ß-lactamase produsing resistance to ceftazidime, ampicillins and ?-lactamase inhibitors. Antimicrob. Agents Chemother. 2002, 46, 646-653.
Vakulenko S., Golemi D., Geryk B., Souvorov M., Knox J., Mobashery S.,Lerner S. Mutational replacement of Leu-293 in the class C Enterobacter cloacae P99 ß-lactamase confers increased MIC of cefepime. Antimicrob. Agents Chemother. 2002, 46, 1966-1970.
Golemi D., Maveyraud L., Vakulenko S., Tranier S., Samama J. P., Mobashery S. Critical involvement of carbamylated lysine in catalytic function of class D ß-lactamases. Proc. Natl. Acad. Sci. USA. 2001, 98, 14280-14285.
Nagase T., Golemi D., Ishiwata A., Mobashery S. Inhibition of ß-lactamases by 6,6-bis(hydroxymethyl)penicillanate. Bioorg. Chem. 2001, 29, 140-145.
Golemi-Kotra D. and Mobashery S. Emergence of mechanisms of resistance in response to the challenge of antibiotics. Encyclopedia on-line, 2002.
Maveyraud L., Golemi D., Vakulenko S., Tranier S., Ishiwata A., Kotra L. P., Mobashery S., Samama J. P. Insights into the class D ß-lactamases are revealed by the crystal structure of the OXA-10 enzyme in Pseudomonas aeruginosa. Structure. 2000, 8, 1289-1298.
Golemi D., Maveyraud L., Vakulenko S., Tranier S., Ishiwata A., Kotra L. P.,Samama J. P., Mobashery S. The first structural and mechanistic insights for class D ?-lactamases: Evidence for a novel catalytic process for turnover of ß-lactam antibiotics. J. Am. Chem. Soc. 2000, 122, 6132-6133.