Indole Based Weapons to Fight Antibiotic Resistance: A Structure–Activity Relationship Study

Abstract

Antibiotic resistance represents a worldwide concern, especially regarding the outbreak of methicillin-resistant Staphylococcus aureus, a common cause for serious skin and soft tissues infections. A major contributor to Staphylococcus aureus antibiotic resistance is the NorA efflux pump, which is able to extrude selected antibacterial drugs and biocides from the membrane, lowering their effective concentrations. Thus, the inhibition of NorA represents a promising and challenging strategy that would allow recycling of substrate antimicrobial agents. Among NorA inhibitors, the indole scaffold proved particularly effective and suitable for further optimization. In this study, some unexplored modifications on the indole scaffold are proposed. In particular, for the first time, substitutions at the C5 and N1 positions have been designed to give 48 compounds, which were synthesized and tested against norA-overexpressing S. aureus. Among them, 4 compounds have NorA IC50 values lower than 5.0 μM proving to be good efflux pump inhibitor (EPI) candidates. In addition, preliminary data on their ADME (absorption, distribution, metabolism, and excretion) profile is reported.

Searching for Novel Inhibitors of the S. aureus NorA Efflux Pump: Synthesis and Biological Evaluation of the 3‐Phenyl‐1,4‐benzothiazine Analogues

“…The lack of the crystal structure for NorA and the structural heterogeneity of known NorA EPIs– prompted us to pursue a classical medicinal chemistry approach entailing modifications of the benzothiazine nucleus aimed at the substitution of the sulfur atom with the goals being to: 1) resolve the chemical stability issues, 2) retain the EPI activity, and 3) contribute to better delineate the SAR of this class of NorA EPIs. Thus, the sulfur atom at position 1 of the 2 H ‐benzo[1,4]thiazine scaffold was substituted by oxygen (‐ O ‐), nitrogen (‐NH‐), or a methylene unit (‐CH 2 ‐) to obtain the corresponding 3‐phenyl‐2 H ‐benzo[1,4]oxazine ( 1 ), 2‐phenyl‐1,2,3,4‐tetrahydroquinoxaline ( 2 ), and 2‐phenyl‐1,2,3,4‐tetrahydroquinoline ( 3 ) nuclei, respectively.…”

Assessments of iodoindoles and abamectin as inducers of methuosis in pinewood nematode, Bursaphelenchus xylophilus

“…Previous reports have established that indole based therapies provide potential means of addressing antibiotic resistance and cancer progression 55 . Furthermore, indoles serve as promising scaffolds for drug development due to their antibacterial, anticancer, anti-oxidant, anti-inflammatory, anti-diabetic, antiviral, antiproliferative, and antituberculosis activities 56, 57 .…”

Development of ebsulfur analogues as potent antibacterials against methicillin-resistant Staphylococcus aureus

“…Among them, the compound 5-nitro-2-phenyl-(1H)-indole was discovered as a NorA, efflux pump, inhibitor at IC 50 values lower than 5.0 μM. 5 We also reported 6″-thioether tobramycin and kanamycin B analogues with long linear alkyl chains disrupting bacterial cell membranes and displaying good activity against S. aureus strains. 6–8 Another compound, AFN-125, was found to selectively inhibit S. aureus enoyl-ACP reductase, and has even been tested in clinical trials.…”