Abstract Broad-Spectrum Activity of Antimicrobial Peptoids † Gill Diamond 1, * , Erika Figgins 1 , Denny Gao 1 , Annelise E. Barron 2 and Kent Kirshenbaum 3 1 2 3 * † Citation: Diamond, G.; Figgins, E.; Gao, D.; Barron, A.E.; Kirshenbaum, K. Broad-Spectrum Activity of Department of Oral Immunology and infectious Diseases, School of Dentistry, University of Louisville, Louisville, KY 40202, USA Department of Bioengineering, Stanford University, Palo Alto, CA 94305, USA Department of Chemistry, New York University, New York, NY 10003, USA Correspondence: gill.diamond@louisville.edu Presented at the 8th International Electronic Conference on Medicinal Chemistry, 1–30 November 2022; Available online: https://ecmc2022.sciforum.net/. Abstract: Antimicrobial peptides (AMPs) are naturally occurring host defense molecules, representing an evolutionarily ancient, innate immune mechanism against pathogenic infection. As such, many of these predominantly cationic and amphipathic peptides have been examined for their potential as anti-infective agents. AMP families such as the defensins and cathelicidins exhibit broad-spectrum antimicrobial activity against a wide variety of bacteria, fungi and viruses, initially and predominantly by disruption of the microbial membrane. Due to this physical mechanism, development of resistance by the pathogen is rare. Thus, they represent a great potential for a new type of anti-infective agent. However, due to a variety of reasons, including protease sensitivity and poor bioavailability, they have not been developed into actual therapeutics. To circumvent these issues, we have examined the potential for small molecule mimetics of AMPs, which would be protease-resistant and have better bioavailability. We previously demonstrated the activity of one such class of mimetics, sequence-specific N-substituted glycine oligomers, or peptoids, against the human viral pathogen Herpes Simplex Virus-1 (HSV-1), as well as some bacteria. Here, we compare the activity, both in vitro and in vivo, of select peptoids against bacteria, fungi and viruses, to begin to study the structure/activity relationship with a broad spectrum of microbial pathogens. Our results show that some peptoid structures are more active against one type of pathogen than another. However, at least two of the tested peptoids exhibit potent activity against Gram positive bacteria, Gram negative bacteria, fungi and viruses. Our results suggest that these molecules can be developed into potent broad-spectrum antimicrobial agents. Antimicrobial Peptoids. Med. Sci. Forum 2022, 14, 122. https:// Keywords: Antibiotics; antivirals; antifungals; peptide mimetics doi.org/10.3390/ECMC2022-13491 Academic Editor: Maria Emília Sousa Published: 4 November 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Materials: The presentation material of this work is available online at https:// www.mdpi.com/article/10.3390/ECMC2022-13491/s1. Author Contributions: Conceptualization, G.D., K.K. and A.E.B.; methodology, E.F. and D.G.; writing, G.D., K.K. and A.E.B. All authors have read and agreed to the published version of the manuscript. Funding: This work was funded by a grant from Maxwell Biosciences to G.D.; and from the US Public Health Services to A.E.B. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: K.K. is Chief Scientific Officer of Maxwell Biosciences; A.E.B. is a shareholder and member of the Board of Directors for Maxwell Biosciences; G.D. is a shareholder and consultant for Maxwell Biosciences; The funders had no role in the design of this study, the collection of data or the writing of the manuscript. Med. Sci. Forum 2022, 14, 122. https://doi.org/10.3390/ECMC2022-13491 https://www.mdpi.com/journal/msf