Abstract
There is an urgent need for new antimicrobials to treat the opportunistic Gram-negative Burkholderia cenocepacia, which represents a problematic challenge for cystic fibrosis patients. Recently, a benzothiadiazole derivative, C109, was shown to be effective against the infections caused by B. cenocepacia and other Gram-negative and-positive bacteria. C109 has a promising cellular target, the cell division protein FtsZ, and a recently developed PEGylated formulation make it an attractive molecule to counteract Burkholderia infections. However, the ability of efflux pumps to extrude it out of the cell represents a limitation for its use. Here, more than 50 derivatives of C109 were synthesized and tested against Gram-negative species and the Gram-positive Staphylococcus aureus. In addition, their activity was evaluated on the purified FtsZ protein. The chemical, metabolic and cellular stability of C109 has been assayed using different biological systems, including quantitative single-cell imaging. However, no further improvement on C109 was achieved, and the role of efflux in resistance was further confirmed. Also, a novel nitroreductase that can inactivate the compound was characterized, but it does not appear to play a role in natural resistance. All these data allowed a deep characterization of the compound, which will contribute to a further improvement of its properties.
Highlights
Cystic fibrosis (CF) patients are continuously subjected to antibiotic therapies due to lung colonization both by Gram-positive and –negative bacteria
New antibacterials are highly necessary, their development may be limited by poor commercial interest in Burkholderia infections because they are rare, with approximately 2.6% of CF patients infected with these bacteria
We found that the benzothiadiazole derivative C109 is highly effective against B. cenocepacia (Scoffone et al, 2015) and other Gram-negative and-positive bacteria, including Mycobacterium abscessus (Hogan et al, 2018)
Summary
Cystic fibrosis (CF) patients are continuously subjected to antibiotic therapies due to lung colonization both by Gram-positive and –negative bacteria. Among the latter, Burkholderia cenocepacia represents a main concern being responsible for the so-called “cepacia syndrome,” a necrotizing pneumonia which can lead to patient’s death (Salsgiver et al, 2016). C109 Derivatives important characteristic, which renders these bacteria dangerous, is their resistance toward most antibiotics used in clinical practice (Scoffone et al, 2017) This limits the therapeutic options available to treat the infections, and there are no standardized set of antibiotics for treatment. New antibacterials are highly necessary, their development may be limited by poor commercial interest in Burkholderia infections because they are rare, with approximately 2.6% of CF patients infected with these bacteria (https://www.cff. org/Research/Researcher-Resources/Patient-Registry/)
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