Optimization of a Benzothiazole Indolene Scaffold Targeting Bacterial Cell Wall Assembly

Abstract

Background

The bacterial cell envelope is comprised of the cell membrane and the cell wall. The bacterial cell wall provides rigidity to the cell and protects the organism from potential harmful substances also. Cell wall biosynthesis is an important physiological process for bacterial survival and thus has been a primary target for the development of antibacterials. Antimicrobial peptides that target bacterial cell wall assembly are abundant and many bind to the essential cell wall precursor molecule Lipid II.

Methods

We describe the structure-to-activity (SAR) relationship of an antimicrobial peptide-derived small molecule 7771–0701 that acts as a novel agent against cell wall biosynthesis. Derivatives of compound 7771–0701 (2-[(1E)-3-[(2E)-5,6-dimethyl-3-(prop-2-en-1-yl)-1,3-benzothiazol-2-ylidene]prop-1-en-1-yl]-1,3,3-trimethylindol-1-ium) were generated by medicinal chemistry guided by Computer-Aided Drug Design and NMR. Derivatives were tested for antibacterial activity and Lipid II binding.

Results

Our results show that the N-alkyl moiety is subject to change without affecting functionality and further show the functional importance of the sulfur in the scaffold. The greatest potency against Gram-positive bacteria and Lipid II affinity was achieved by incorporation of a bromide at the R3 position of the benzothiazole ring.

Conclusion

We identify optimized small molecule benzothiazole indolene scaffolds that bind to Lipid II for further development as antibacterial therapeutics.

Keywords:

• Lipid II
• antibiotics
• drug development
• cell wall

Abbreviations

S. aureus, Staphylococcus aureus; E. faecium, Enterococcus faecium; MIC, Minimal Inhibitory Concentration; MurNAc, N-acetyl muramic acid.

Author Contributions

All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Funding

This work was supported by Center for Biomolecular Therapeutics (PR155EDL1; UMB), the UMB Computer-Aided Drug Design Center, a UM Ventures Seed grant and Center for Maryland Advanced Ventures grant to EdL.

Disclosure

AM Jr and EdL are inventors on US patents # 8,796,323 and # 9,351,963 to University of Maryland, Baltimore; JC, SF, AM Jr and EdL are inventors on PCT/US11/59432. AM Jr is a co-founder and CSO for SilcsBio LLC. The authors report no other conflicts of interest in this work.