Marcelo Tolmasky

 

Photograph of Marcelo TolmaskyNovel 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)

Cuajungco, M. P., Ramirez, M. S., & Tolmasky, M. E. (2021). Zinc: Multidimensional Effects on Living Organisms. Biomedicines, 9(2). doi:10.3390/biomedicines9020208

Jani, S., Ramirez, M. S., & Tolmasky, M. E. (2021). Silencing Antibiotic Resistance with Antisense Oligonucleotides. Biomedicines, 9(4). doi:10.3390/biomedicines9040416

Magallon, J., Vu, P., Reeves, C., Kwan, S., Phan, K., Oakley-Havens, C. L., . . . Tolmasky, M. E. (2021). Amikacin in combination with zinc pyrithione prevents growth of a multidrug-resistant carbapenem-resistant Klebsiella pneumoniae isolate. Int J Antimicrob Agents, 58(5), 106442. doi:10.1016/j.ijantimicag.2021.106442

Magallon, J., Vu, P., Reeves, C., Kwan, S., Phan, K., Oakley-Havens, C. L., . . . Tolmasky, M. E. (2022). Amikacin potentiator activity of zinc complexed to a pyrithione derivative with enhanced solubility. Sci Rep, 12(1), 285. doi:10.1038/s41598-021-04724-4

Magana, A. J., Sklenicka, J., Pinilla, C., Giulianotti, M., Chapagain, P., Santos, R., . . . Tolmasky, M. E. (2023). Restoring susceptibility to aminoglycosides: identifying small molecule inhibitors of enzymatic inactivation. RSC Med Chem, 14(9), 1591-1602. doi:10.1039/d3md00226h

Ngo, D., Magana, A. J., Tran, T., Sklenicka, J., Phan, K., Eykholt, B., . . . Tolmasky, M. E. (2023). Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions. Pharmaceuticals (Basel), 16(2). doi:10.3390/ph16020236

Ramirez, M. S., Bonomo, R. A., & Tolmasky, M. E. (2020). Carbapenemases: Transforming Acinetobacter baumannii into a Yet More Dangerous Menace. Biomolecules, 10(5). doi:10.3390/biom10050720

Reeves, C. M., Magallon, J., Rocha, K., Tran, T., Phan, K., Vu, P., . . . Tolmasky, M. E. (2020). Aminoglycoside 6'-N-acetyltransferase Type Ib [AAC(6')-Ib]-Mediated Aminoglycoside Resistance: Phenotypic Conversion to Susceptibility by Silver Ions. Antibiotics (Basel), 10(1). doi:10.3390/antibiotics10010029

Traglia, G., Ramirez, M. S., & Tolmasky, M. E. (2023). Role of Xer site-specific recombination in the genesis of pJHCMW1: an evolutionary hypothesis. J Glob Antimicrob Resist, 34, 199-201. doi:10.1016/j.jgar.2023.07.017

Traglia, G. M., Pasteran, F., Escalante, J., Nishimura, B., Tuttobene, M. R., Subils, T., . . . Ramirez, M. S. (2023). Genomic Comparative Analysis of Two Multi-Drug Resistance (MDR) Acinetobacter baumannii Clinical Strains Assigned to International Clonal Lineage II Recovered Pre- and Post-COVID-19 Pandemic. Biology (Basel), 12(3). doi:10.3390/biology12030358