Abstract
Filamentous temperature-sensitive Z (FtsZ) is a prokaryotic protein with an essential role in the bacterial cell division process. It is widely conserved and expressed in both Gram-positive and Gram-negative strains. In the last decade, several research groups have pointed out molecules able to target FtsZ in Staphylococcus aureus, Bacillus subtilis and other Gram-positive strains, with sub-micromolar Minimum Inhibitory Concentrations (MICs). Conversely, no promising derivatives active on Gram-negatives have been found up to now. Here, we report our results on a class of benzamide compounds, which showed comparable inhibitory activities on both S. aureus and Escherichia coli FtsZ, even though they proved to be substrates of E. coli efflux pump AcrAB, thus affecting the antimicrobial activity. These surprising results confirmed how a single molecule can target both species while maintaining potent antimicrobial activity. A further computational study helped us decipher the structural features necessary for broad spectrum activity and assess the drug-like profile and the on-target activity of this family of compounds.
Highlights
Antimicrobial resistance is a major cause of concern for public health worldwide, with the ever-growing diffusion of multidrug resistant pathogens and the consequent narrowing down of therapeutic options for previously treatable infections.Antibiotics 2020, 9, 160; doi:10.3390/antibiotics9040160 www.mdpi.com/journal/antibioticsAccording to a recent report by the Centers for Disease Control and Prevention (CDC), the grim predictions of a “post-antibiotic era” have come true, with an estimated over 3 million infections and nearly 50,000 deaths related to drug resistance per year in the U.S alone [1]
We previously prepared and tested the chromanes IV and V, the tetrahydronapthalene VI [22], the benzoxazines VII and VIII and the tetrahydroquinoxaline IX [23]. None of these modifications resulted in a positive outcome for the antimicrobial activity
Compounds 1–8 were designed starting from the chemical structure of III, modifying the heteroatoms of the 1,4-benzodioxane ring for 1–6, or lengthening the distance between the benzodioxane and the benzamide moieties for 7 and 8 (Figure 2)
Summary
Antimicrobial resistance is a major cause of concern for public health worldwide, with the ever-growing diffusion of multidrug resistant pathogens and the consequent narrowing down of therapeutic options for previously treatable infections. Benzodioxane-benzamides I and II [12]) are summarized, together with some relevant details They all target the essential bacterial cell division protein FtsZ, a protein widely distributed among Gram-positive and Gram-negative strains, with which they interact at two different binding sites (the GTP-binding site for Z2 and Z3, and the interdomain site for the others, which are better explained below). FtsZ [18,19,20], inhibitors, previously mentioned researchers considered the insights coming from previous studies [18,19,20], inthe which was shown how thethe genetic inactivation ofRND pumps resulted in increased. 2020, 9, pumps resulted in increased activity for a variety of other drugs This finding strongly supports thethe role of these efflux systems in both intrinsic and acquired resistance for these microorganisms.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
