New benzyldiazepane derivatives able to reduce biofilm formation in Escherichia coli

Antimicrobial resistance (AMR) represents a serious problem for human health and arises through several mechanisms. Bacteria can further enhance their intrinsic resistance by forming biofilms, defensive barriers that protect bacterial cells from antibiotics and the host immune system. Moreover, sub-inhibitory concentrations of antibiotics, such as chloramphenicol (CHL), stimulate biofilm development. A valid strategy to counteract biofilm-associated resistance is the use of biofilm formation inhibitors. For this purpose, a series of benzyldiazepane derivatives was synthesized as new anti-biofilm agents. First, their minimum inhibitory concentration (MIC) values and their effect with CHL on bacterial growth inhibition were evaluated. Then, each molecule was studied alone and in combination with sub-inhibitory concentrations of CHL to assess its ability to inhibit biofilm formation in the Escherichia coli K-12 strain. Four compounds showed intrinsic anti-biofilm activity and, interestingly, a combinatorial effect with CHL was observed for almost all derivatives. Overall, the results highlight benzyldiazepane as a promising scaffold for the development of anti-biofilm agents, since the tested compounds were able to decrease biofilm formation. In particular, the nitrobenzyl derivative 2 significantly reduced biofilm formation both alone and in combination with CHL.