Universitą degli studi di Pavia
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Udine research activity
Searching for new drugs and new molecular targets in Burkholderia cenocepacia
Burkholderia cenocepacia is a Gram-negative opportunistic pathogen, belonging to the Burkholderia cepacia complex (Bcc). The Bcc comprises at least 17 taxonomically related species, which have spread to diverse niches from the natural environment and humans. In particular, they have emerged as pathogens in patients with Cystic Fibrosis (CF), chronic granulomatous disease, and in immunocompromised individuals. Bcc bacteria emerged as serious CF pathogens about 30 years ago, particularly, B. cenocepacia is able to infect the epithelium of the respiratory tract of CF patients, often leading to “cepacia syndrome”, characterized by necrosis, sepsis, and death. Despite the heavy use of antibiotics, infections caused by B. cenocepacia are very difficult to eradicate. This microorganism is intrinsically resistant to many antibiotics such as aminoglycosides, cephalosporins, polymyxins and β-lactams. Currently, there is an urgent need for new antibiotics to make the chemotherapy more effective and to overcome the problem of drug-resistant strains. Moreover, there is also the necessity to identify new drug targets. For these reasons my project is focused on testing new molecules to find drugs against B. cenocepacia J2315 more effective than the existing ones and on the identification of their mechanism of action.
In collaboration with Prof. Vadim Makarov, a chemist of the “State Research Center for Antibiotics” of Moscow, a new promising compound was found, showing a minimal inhibitory concentration (MIC) of 16 μg/ml. In order to identify which mutations confer the resistance, spontaneous resistant mutants were isolated and their genome were sequenced through Illumina technology. Untill now we identified a mechanism of resistance, that is the overexpression of the operon BCAL2820-BCAL2822. This operon encodes an efflux system belonging to the family of RND transporter (Resistance Nodulation cell Division), which are known to be involved in antibiotic resistance. This result is important for the chemist that can improve the drug structure to avoid the interactions between efflux systems and the molecule.
Burkholderia cenocepacia is a Gram-negative opportunistic pathogen, belonging to the Burkholderia cepacia complex (Bcc). The Bcc comprises at least 17 taxonomically related species, which have spread to diverse niches from the natural environment and humans. In particular, they have emerged as pathogens in patients with Cystic Fibrosis (CF), chronic granulomatous disease, and in immunocompromised individuals. Bcc bacteria emerged as serious CF pathogens about 30 years ago, particularly, B. cenocepacia is able to infect the epithelium of the respiratory tract of CF patients, often leading to “cepacia syndrome”, characterized by necrosis, sepsis, and death. Despite the heavy use of antibiotics, infections caused by B. cenocepacia are very difficult to eradicate. This microorganism is intrinsically resistant to many antibiotics such as aminoglycosides, cephalosporins, polymyxins and β-lactams. Currently, there is an urgent need for new antibiotics to make the chemotherapy more effective and to overcome the problem of drug-resistant strains. Moreover, there is also the necessity to identify new drug targets. For these reasons my project is focused on testing new molecules to find drugs against B. cenocepacia J2315 more effective than the existing ones and on the identification of their mechanism of action.
In collaboration with Prof. Vadim Makarov, a chemist of the “State Research Center for Antibiotics” of Moscow, a new promising compound was found, showing a minimal inhibitory concentration (MIC) of 16 μg/ml. In order to identify which mutations confer the resistance, spontaneous resistant mutants were isolated and their genome were sequenced through Illumina technology. Untill now we identified a mechanism of resistance, that is the overexpression of the operon BCAL2820-BCAL2822. This operon encodes an efflux system belonging to the family of RND transporter (Resistance Nodulation cell Division), which are known to be involved in antibiotic resistance. This result is important for the chemist that can improve the drug structure to avoid the interactions between efflux systems and the molecule.
