Novel technologies to combat antibiotic resistance
Drug resistance is a major clinical and public health problem. Every year tens of thousands of deaths are caused by resistant infections in the USA and the number of infected people is more than ten times higher. The problem is equally or more serious in the rest of the world. Several nosocomial and community acquired pathogens have become resistant to many different antibiotics seriously complicating treatment and in some cases becoming virtually untreatable. Besides establishing policies to limit the increase in resistant strains, there is an urgent need for research to find new antimicrobial agents and preserve the effectiveness of currently available antibiotics. We use as model system the resistance to amikacin mediated by the the aminoglycoside 6’-N-acetyltransferase type Ib [AAC(6’)-Ib]. Relevant facts about this model are:
• Amikacin is a very useful antibiotic refractory to several modifying enzymes. Furthermore it is of special utility in the treatment of suspected or confirmed neonatal infections. However, in the past years resistance has increased dangerously in certain parts of the world and the resistant strains are disseminating.
• The aac(6’)-Ib gene is present in over 70% of AAC(6’)-I-producing gram-negative clinical isolates including Acinetobacter, Pseudomonas, Klebsiella and E. coli.
• While there are several antimicrobials in development to treat drug resistant gram-positive pathogens, the number is critically smaller for drug resistant gram-negatives such as Klebsiella or Acinetobacter.
Our approach is two-pronged:
1) We study basic aspects of the resistance mediated by aac(6’)-Ib and mechanisms of its dissemination. We expect that the knowledge gained will be the basis for developing new antimicrobial agents.
2) We are using antisense technologies to interfere with expression of the resistance gene and prolong the usefulness of amikacin.
Selected publications (Click for full list)
T. Tran, D. J. Sherratt, and M. E. Tolmasky. fpr, a deficient Xer recombination site from a Salmonella plasmid, fails to confer stability by dimer resolution: comparative studies with the pJHCMW1 mwr site. Journal of Bacteriology 2010 192 883-887
A. J. C. Soler Bistué, F. Martín, N. Vozza, H Ha, J. Joaquín, A. Zorreguieta, and M. E. Tolmasky. Inhibition of aac(6')-Ib-mediated amikacin resistance by nuclease resistant external guide sequences in bacteria. Proceedings of the National Academy of Sciences of USA 2009 106 13230-13235
S. Trigueros, T. Tran, N. Sorto, J. Newmark, S. Colloms, D. J. Sherratt, and M. E. Tolmasky. mwr Xer site-specific recombination is hypersensitive to DNA supercoiling. Nucleic Acids Research 2009 37 3580-3587
M. S. Ramirez, T. R. Parenteau, D. Centrón, and M. E. Tolmasky. Functional Characterization of Tn1331 Gene Cassettes. Journal of Antimicrobial Chemotherapy 2008 62 669-673
A. J. C. Soler Bistué, D. Birshan, A. P. Tomaras, M. Dandekar, T. Tran, J. Newmark, D. Bui, N. Gupta, K. Hernandez, R. Sarno, A. Zorreguieta, L. A. Actis, and M. E. Tolmasky. Klebsiella pneumoniae multiresistance plasmid pMET1: similarity with the Yersinia pestis plasmid pCRY and integrative conjugative elements. PLoS ONE 2008 3 e1800
A. J. C. Soler Bistué, H. Ha, R. Sarno, M. Don, A. Zorreguieta, and M. E. Tolmasky. External guide sequences targeting the aac(6’)-Ib mRNA induce inhibition of amikacin resistance. Antimicrobial Agents and Chemotherapy 2007 51 1918-1925