Innovative Methods in Post-Microbial Antibiotic Design

Innovative Methods in Post-Microbial
Antibiotic Design: Double Alkylation,
Cooperative Wedges, Pseudo-Complex
Assemblies, and Affinity-Driven Immune
Activation
Yaroslav Grigorievich Zaitsev ORCID: 0000-0002-0069-2997
Preprint · December 2025
Abstract
This work proposes four advanced strategies for the development of post-microbial
antibiotics and antiviral agents: (1) conformation-dependent double alkylation—a covalent
two-step locking mechanism; (2) cooperative molecular wedges—multi-ligand denaturation
via synergistic binding; (3) pseudo-complex assemblies on biopolymers—self-organizing
mimetics of complex hormones; and (4) affinity-driven macrophage activation—surface
decoration of pathogens with immunogenic patterns to trigger innate immune clearance. All
approaches integrate conformational protein dynamics, artificial intelligence-driven molecular
design, and modern computational tools to achieve unprecedented selectivity, low resistance
potential, and novel therapeutic mechanisms.
Keywords: antibiotic design, post-microbial strategies, covalent inhibitors, protein
denaturation, immune activation, artificial intelligence in drug discovery
1. Introduction
The global rise of antimicrobial resistance necessitates a paradigm shift in antibiotic
development [1]. Traditional antibiotics, derived from or inspired by microbial natural
products, share fundamental limitations including insufficient selectivity and rapid emergence
of resistance. This work presents a framework for post-microbial antibiotic design that moves
beyond mimicking natural antimicrobials to leveraging physical principles of protein structure,
dynamics, and host-pathogen interactions. We propose four complementary strategies that
collectively represent a new frontier in antimicrobial therapy. The article is a compilation of
material from the author’s previous articles.