Synthesis and biological evaluation of naturally and non-naturally occurring halogenated analogues of N-acyl homoserine lactones as quorum sensing modulators

Many Gram-negative bacteria secrete N-acylated homoserine lactones (AHLs) in order to control the expression of specific target genes important for phenotype expression in a process known as quorum sensing (QS). The importance of QS for virulence/ biofilm development in pathogenic bacteria nowadays is obvious. Therefore, disruption of QS by synthetic analogues or enzymatic modulation is seen as a new anti-infective and antifouling strategy. In aquatic environments, bacteria interact in various ways with other organisms as pathogens, symbionts or competitors in the search for resources. Many marine organisms have developed defence or deterrence mechanisms, which are often involved in the production of small diffusible signal molecules that can interfere with the QS systems. Diatoms are known to produce a variety of halogenated compounds. Bio-halogenation in nature is linked to haloperoxidase activity. In this study, synthetic routes and biological evaluation of a wide library of novel naturally and non-naturally occurring halogenated AHL analogues, in which chlorine, bromine or iodine atom(s) were introduced at the α-carbon, are presented. Furthermore, the H2O2-dependent inactivation and degradation pathway of a type of QS molecules, i.e. N-β-ketoacylated homoserine lactones, by a natural haloperoxidase system from the benthic diatom Nitzschia cf pellucida is discussed. Bioactivity of these halogenated AHL analogues was directly compared with a broad library of natural AHLs