Synthesis of new carolacton derivatives and their activity against biofilms of oral bacteria

Abstract

Carolacton, a secondary metabolite isolated from the extracts of Sorangium cellulosum, causes membrane damage and cell death in biofilms of the caries-and endocarditis-associated bacterium Streptococcus mutans. Here, we report the total synthesis of several derivatives of carolacton. All new structural modifications introduced abolished its biological activity, including subtle ones, such as inversion of configuration at C9. However, a bicyclic bislactone derivative as well as the methyl ester of carolacton resulted in compounds with prodrug properties. Their inhibitory activity on S. mutans was proven to be based on enzymatic hydrolysis by S. mutans which provided native carolacton resulting in biofilm damage in vivo. Moreover, we demonstrate that carolacton acts also on S. gordonii, S. oralis and the periodontitis pathogen Aggregatibacter actinomycetemcomitans, causing elongated cells and growth inhibition.

Natural Products as Platforms To Overcome Antibiotic Resistance

“…289 Given that each of these could be hydrolyzed to yield carolacton, it was hypothesized that these derivatives were merely acting as pro-drugs. Kirschning and co-workers did indeed detect small quantities of carolacton in the supernatant, indicating a weak pro-drug effect.…”

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms

“…9 Kirschning in particular has been quite prolific as they have disclosed both the first total synthesis 10 and uncovered useful information regarding the structure—activity relationship (SAR) by analog synthesis (Figure 1). 11 These studies elucidated that both drastic (increased ring size) and even small conformational changes to the 12-membered macrocycle, for example, introduction of an α,β -unsaturated ketone or an epimeric allylic alcohol, abolish activity. Further, the side chain ketone was thought to be essential and “pro-drug” ester derivatives affected biofilm development at concentrations relative to their rate of hydrolysis indicating that carolacton, and not the analogs, were responsible for activity.…”

“…Of note, these analogs contain a carboxylic acid that appears to be important for bioactivity as the corresponding alcohols are inactive (Figure S1), consistent with the findings of Kirschning. 11 …”

Twelve‐membered macrolactones: privileged scaffolds for the development of new therapeutics

“…Interestingly, the methyl ester variant ( 127 ) and bis‐macrolactone ( 129 ) analogs displayed activity comparable to carolacton itself. It was shown that these compounds act as pro‐drugs, being hydrolyzed in vivo by S. mutans hydrolase enzymes to generate carolacton, thereby restoring bioactivity . Taken together, these findings demonstrate the highly specific interaction of carolacton with its biological target and provide valuable information to guide future analog development.…”

“…The Kirschning group has also reported the synthesis of several carolacton analogs, providing useful SAR information (Figure ). The methyl ester derivatives 127 and 128 were obtained by modification of carolacton itself.…”