Covalent Inhibitors of Pathogenic Bacterial, Protozoal, Viral, and Fungal Targets

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: 31 December 2025 | Viewed by 810

Special Issue Editors


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Guest Editor
Department of Chemistry, American University, Washington, DC 20016, USA
Interests: organic synthesis; fragment-based drug discovery; cross inhibition of prokaryotic systems

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Guest Editor
Department of Microbiology and Immunology, Midwestern University, Downers Grove, IL 60515, USA
Interests: effect of physiologic oxygen levels on metabolism of both prokaryotes and eukaryotes and their response to chemotherapeutic agents; biofilm formation and dispersal

Special Issue Information

Dear Colleagues,

Most FDA-approved drugs bind reversibly, with noncovalent interactions to their corresponding macromolecular targets. Most early covalent drugs were discovered serendipitously, exerting their (inhibitory) activity by binding to active enzyme sites. Therefore, early covalent drugs often mimic a substrate transition state to enable covalent modification of a catalytic amino acid residue. Historically, further investigation on developing enzymes’ covalent modulators has been limited due to concerns about their potential lack of selectivity.  However, in the last three decades, targeted covalent modulators, the vast majority being inhibitors (TCIs), have increased in popularity among drug candidates and chemical probes. Covalent labeling has multiple advantages as a tool in probe and drug development. Compared with noncovalent inhibitors, targeted covalent modulators can provide increased selectivity, potency, and prolonged modulation of target function. Covalent conjugation has inhibited targets at protein–protein interactions (PPIs) previously considered undruggable. Approval of an array of covalent drugs across several indications, primarily focused on cancer therapy by the FDA, demonstrates the promise of the rational design of covalent drugs in targeting non-catalytic/non-conserved amino acids to increase selectivity has become a reality. The covalent inhibitor conjugation is currently dominated by thiol-reactive electrophiles that react with cysteines. The development of chemical warheads that target amino acids differently from the cysteines has also started and undoubtedly will further expand the utility of TCIs.

We invite colleagues investigating covalent modulators for the pathogenic bacterial, protozoal, viral, and fungal biological targets (enzymes) to submit their manuscripts to this Special Issue as original research (preferred) and reviews.

Dr. Monika I. Konaklieva
Dr. Balbina J. Plotkin
Guest Editors

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Keywords

  • covalent inhibitors
  • pathogenic bacterial and viral protein targets
  • protozoa
  • fragment-based drug discovery
  • chemical warheads
  • prodrugs
  • STD NMR
  • MS
  • SITE (single-injection thermal extinction)

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Published Papers (1 paper)

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Review

25 pages, 4524 KiB  
Review
N-Organothio β-Lactams Offer New Opportunities for Controlling Pathogenic Bacteria
by Edward Turos
Pathogens 2025, 14(7), 628; https://doi.org/10.3390/pathogens14070628 - 24 Jun 2025
Viewed by 505
Abstract
Pathogenic bacteria such as the drug-resistant strains of Staphylococcus aureus dominate our medical and environmental landscape, causing hundreds of thousands of deaths from infections and life-threatening complications following surgeries. The availability of antibiotics and treatment protocols to control these microbes are becoming increasingly [...] Read more.
Pathogenic bacteria such as the drug-resistant strains of Staphylococcus aureus dominate our medical and environmental landscape, causing hundreds of thousands of deaths from infections and life-threatening complications following surgeries. The availability of antibiotics and treatment protocols to control these microbes are becoming increasingly more limited as antibiotic resistance becomes more prevalent. In this article, a new family of small molecules referred to as N-organothio β-lactams is presented that have unique features and a mode of action against these pathogenic microbes, including multi-drug resistant strains, that may offer new options to address these concerns. This review gives an overview of the initial discovery, exploration and ongoing development of these synthetic antibacterial agents, with a focus on their unique properties and capabilities that provide fresh opportunities for combating pathogenic bacteria. Full article
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