<p>Indole-core-based novel antibacterial agent targeting FtsZ</p>

Abstract

Background The prevalence of drug-resistant bacterial infections urges the development of new antibacterial agents that possess a mechanism of action different from traditional antibiotics. FtsZ has been recognized as a key functional protein in bacterial cell division and it is currently believed to be a potential target for the development of novel antibacterial agents. Purpose The primary aim of the study is to screen out an inhibitor targeting at FtsZ and followed to investigate its antibacterial activity and mode of action. Methods Cell-based cell division inhibitory screening assay, antimicrobial susceptibility test, minimum bactericidal concentration assay, time-killing curve determination, FtsZ polymerization assay, GTPase activity assay, and molecular modeling were performed in the present study. Results The screening study from a small library consisting of benzimidazole and indole derivatives discovered a compound (CZ74) with an indole-core structure. The compound exhibited strong cell division inhibitory effect. In addition, CZ74 shows high antibacterial potency against a number of tested Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus . The minimum inhibitory concentration values obtained were within the range of 2–4 µg/mL. The results of biological study revealed that CZ74 at 2 µg/mL is able to disrupt FtsZ polymerization and inhibit GTPase activity and cell division. From molecular modeling study, CZ74 is found possibly binding into the interdomain cleft of FtsZ protein and then leads to inhibitory effects. Conclusion This indole-cored molecule CZ74 could be a potential lead compound and could be further developed as a new generation of antibacterial agents targeting FtsZ to combat against multidrug-resistant bacteria.

Comprehensive Host Cell-Based Screening Assays for Identification of Anti-Virulence Drugs Targeting Pseudomonas aeruginosa and Salmonella Typhimurium

“…In both infection models, the treatment with various indoline-2-one derivates was associated with an increased host cell survival. As previously described we could not detect any growth-inhibitory effect of indoline-2-ones on Pa or S T. [ 32 ]. However, indole and indoline derivates such as 7-fluoroindole are known to inhibit a series of virulence factors of Pa such as quorum sensing, swarming and synthesis of pyocyanin, pyochelin and pyoverdine [ 29 ].…”

Rapid Killing and Biofilm Inhibition of Multidrug-Resistant Acinetobacter baumannii Strains and Other Microbes by Iodoindoles

“…The efficacies of indole derivatives such as 2, 5, 6-and 2, 5, 7-trisubstituted benzimidazoles in M. tuberculosis, S. aureus, and B. subtilis are reflected by their abilities to target a key functional protein in bacterial cell division like FtsZ. In the same study, it was hypothesized that these derivatives bound in the interdomain cleft of FtsZ, interrupted GTPase activity, stimulated FtsZ polymerization, and ultimately inhibiting bacterial cell division [55]. Since 5-iodoindole decreased cell size of E. coli strains and C. albicans (Figure 8) and was found to rapidly kill A. baumannii (Figure 4), other microbes (Figure 7), three nematode species [24][25][26][27], and an insect [25], but not plants or vertebrates [25,26], it would appear that 5-iodoindole is selectively transported through the membranes of bacteria, fungi, and nematodes and then specifically targets DNA.…”

Indole/isatin‐containing hybrids as potential antibacterial agents

“…Hybrid 93 (MIC: 2.0–4.0 μg/ml) possessed an excellent activity against both drug‐sensitive ( B. subtilis , S. aureus , S. epidermidis , and E. faecalis ) and drug‐resistant (four MRSA, ampicillin‐resistant S. aureus , VRE, and vancomycin‐resistant E. faecium ) strains, and the activity was far superior to that of berberine (MIC: ≥96 μg/ml). [ 194 ] The mechanistic study revealed that hybrid 93 was able to disrupt FtsZ polymerization and inhibit GTPase activity and cell division, so this hybrid could act as a lead compound for the discovery of novel antibacterial agents targeting FtsZ to fight against multidrug‐resistant bacteria.…”