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Disarming resistant bacteria

Team of researchers finds effective drug combination to fight antibiotic resistance

Oeiras, 22.03.12

It has been difficult for the pharmaceutical industry to discover new and efficacious single agent antibiotics to treat bacterial pathogens resistant to current clinically used antibiotics. A team coordinated by Merck researchers was now able to come up with a successful strategy to decoy bacteria: treat them with an antibiotic and a second drug that has a synergistic effect with the antibiotic, potentiating its effect. This promising approach is now published in Science Translational Medicine and the mechanism by which this particular drug combination is actually effective was sorted out with the collaboration of the Lab of Bacterial Cell Biology at ITQB.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital acquired infections and it has been rapidly emerging also among healthy individuals within the community. Many research teams, including some at ITQB, devote their efforts to understanding how bacterial resistance works and hope to contribute to future solutions for this major public health concern. Over the last years, the Lab of Bacterial Cell Biology has been constructing a collection of Staphylococcus aureus strains with fluorescently tagged proteins, many of which involved in antibiotic resistance mechanisms, which allows them to know where each protein is located in the bacterial cell. That was precisely what they did in this case: by tracking cell division and cell wall synthesis proteins inside the bacteria, researchers were able to compare what happens when drugs are used alone or in combination, showing that the synergy is effective because one of the drugs (an inhibitor of bacterial cell division) causes the delocalization of the target protein for the second drug (a beta-lactam antibiotic). The consequence is that bacteria can no longer divide normally, even though they are genetically resistant to the antibiotic.

Testing drug combinations for overcoming antibiotic resistance is being pursued by many groups. What this work shows is that it is possible to successfully uncover synergistic effects by a rational target-based approach and to use protein localization as a tool to study the mode of action of new antimicrobial compounds.

Original Article

Restoring Methicillin-Resistant Staphylococcus aureus Susceptibility to β-Lactam Antibiotics

Christopher M. Tan, Alex G. Therien,*, Jun Lu, Sang H. Lee1, Alexandre Caron, Charles J. Gill, Christian Lebeau-Jacob, Liliana Benton-Perdomo, João M. Monteiro, Pedro M. Pereira, Nathaniel L. Elsen, Jin Wu, Kathleen Deschamps, Mihai Petcu, Simon Wong, Etienne Daigneault, Susanne Kramer, Lianzhu Liang, Eugene Maxwell, David Claveau, John Vaillancourt, Kathryn Skorey, John Tam, Hao Wang, Timothy C. Meredith, Susan Sillaots, Lisa Wang-Jarantow, Yeeman Ramtohul, Eric Langlois, France Landry, John C. Reid, Gopal Parthasarathy, Sujata Sharma, Anastasia Baryshnikova, Kevin J. Lumb, Mariana G. Pinho, Stephen M. Soisson and Terry Roemer,†

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