Inhibition of Escherichia coli and Bacillus subtilis FtsZ Polymerization and Bacillus subtilis Growth by Dihydroxynaphtyl Aryl Ketones

Abstract

The increasing detection of virulent and/or multidrug resistant bacterial strains makes necessary the development of new antimicrobial agents acting through novel mechanisms and cellular targets. A good choice are molecules aimed to interfere with the cell division machinery or divisome , which is indispensable for bacterial survival and propagation. A key component of this machinery, and thus a good target, is FtsZ, a highly conserved GTPase protein that polymerizes in the middle of the cell on the inner face of the cytoplasmic membrane forming the Z ring, which acts as a scaffold for the recruitment of the divisome proteins at the division site. In this work, we tested the inhibitory effect of five diaryl naphtyl ketone (dNAK) molecules on the in vitro polymerization of both Escherichia coli and Bacillus subtilis FtsZ (EcFtsZ and BsFtsZ, respectively). Among these compounds, dNAK 4 showed the strongest inhibition of FtsZ polymerization in vitro , with an IC 50 of 2.3 ± 0.06 μM for EcFtsZ and 9.13 ± 0.66 μM for BsFtsZ. We found that dNAK 4 binds to GDP-FtsZ polymers but not to the monomer in GTP or GDP state. This led to the polymerization of short and curved filaments, rings, open rings forming clusters, and in the case of BsFtsZ, a novel cylindrical structure of stacked open rings. In vivo , dNAK 4 had almost no effect on the growth of E. coli in liquid culture, in contrast to the strong inhibitory effect observed over B. subtilis growth. The insensitivity of E. coli to this compound is probably related to the impermeability of dNAK 4 to the outer membrane. The low amount of this compound required to inhibit several of the bacterial strains tested and the lack of a cytotoxic effect at the concentrations used, makes dNAK 4 a very good candidate as a starting molecule for the development of a new antibiotic.

Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex

“…Divisome assembly involves sequential and precisely orchestrated protein–protein interactions (PPI) with imbalances ultimately leading to cell death . In Gram-negative bacteria, efforts to target the divisome have focused on the inhibition of FtsZ polymerization in the cytoplasm, which represents one of the initial steps of bacterial cell division (Figure a), however, without providing potent inhibitors. − Consequently, the validation of alternative divisome targets is needed to further explore the potential of divisome inhibition in Gram-negative bacteria.…”

Facile synthesis of graphene wool doped with oleylamine-capped silver nanoparticles (GW-αAgNPs) for water treatment applications

“…The antibacterial activity of GW-αAgNPs and pristine AgNPs was tested against the Gram-negative Pseudomonas aeruginosa CB1 and Gram-positive Bacillus subtilis CN2 strains by the standard micro-dilution method. Earlier reports suggest that P. aeruginosa and B. subtilis strains are capable of adaptive resistance to antibiotics such as penicillin and tetracycline (Araya et al 2019;Pang et al 2019). Figure 8 reveals a dose-dependent reduction in the concentration of Gram-negative Pseudomonas aeruginosa CB1 and Gram-positive Bacillus subtilis CN2 strains after 24 h incubation period as a decrease in turbidity was recorded ).…”

Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division

“…This is consistent with daughter cells that have undergone division but are unable to separate. Grooving has previously been reported in other rodshaped bacteria including B. subtilis, E. coli and P. aeruginosa, when cellular division was arrested (Anderson et al, 2004;de Boer, 2010;Annapurna et al, 2015;Pichoff et al, 2018;Araya et al, 2019;Sharavanan et al, 2019). Complementary time-kill studies were also performed upon A. baumannii ATCC 19606 (Supplementary Figure 1).…”