Katarzyna Pańczyk-Straszak, Karolina Klesiewicz, Paweł Zajdel

Current trends in the fight against antibiotic resistance: a review of selected strategies in advanced preclinical and clinical studies

2025-07-23

Research subject. Antimicrobial resistance is a current challenge in modern medicine, potentially leading to patient deaths from infections caused by drug-resistant bacteria. In response, new treatment strategies are being explored to combat infections caused by bacteria with a high capacity to acquire and develop resistance to antibiotics.

Research objective. The aim of the study was to present selected recent advances in strategies to combat antibiotic resistance, with particular emphasis on approaches based on the use of small-molecule compounds with proven efficacy in clinical trials or in advanced preclinical research.

Materials and methods. A review of scientific literature and clinical trials published between 2015 and 2025 was conducted. Literature sources were searched using the PubMed and Scopus databases, while information on clinical trials was obtained from the ClinicalTrials.gov registry.

Results. Antibacterial peptides represent a promising research direction; however, their clinical application is limited by low bioavailability and high toxicity. In response, a range of compounds is currently being developed, including small-molecule peptides and peptidomimetics that disrupt bacterial cell membranes (e.g., brilacidin), as well as short cyclic peptides such as zosurabalpin, which interact with recently identified proteins responsible for lipopolysaccharide transport across the cell membrane.

Antivirulence compounds, initially used to treat life-threatening diseases driven by virulence factors, are now being proposed for broader use as a third strategy in combating bacterial infections - alongside bactericidal and bacteriostatic therapies (e.g., GSK3882347, fluorothiazinone).

Counteracting the development of antibiotic resistance also involves the use of natural processes occurring within bacterial cells. The so-called "Trojan horse" strategy employs conjugates of traditional antibiotics and synthetic siderophores - chelating agents secreted by bacteria to capture iron ions. For example, cefiderocol binds to membrane receptors of bacterial cells and is subsequently actively transported into the cell. The concept of conjugates is also used in the development of antibiotic-antibody and antibiotic-peptide hybrids with antibacterial activity.

In recent years, a prokaryotic equivalent of targeted protein degradation, known as BacPROTAC technology, has also been developed. It enables the design of molecules that activate protein degradation mechanisms intrinsic to prokaryotic cells, directed against specific bacterial targets. This approach offers the potential for more selective eradication of particular microorganisms, including those highly resistant to currently available antibacterial agents.

Conclusions. The problem of antimicrobial resistance represents one of the most serious challenges facing modern medicine and pharmacy. Currently, advanced preclinical and clinical studies are underway on small-molecule peptides and peptidomimetics, antivirulence agents, conjugates of antibiotics, as well as compounds designed to induce the degradation of essential bacterial proteins. These approaches offer hope for the development and approval of new antibacterial drugs in the future, with a reduced risk of resistance development - an important step toward addressing the global challenge of resistance to currently available antibacterial therapies.

Keywords: antimicrobial resistance, peptidomimetics, conjugates, virulence factors, PROTAC.

© Farm Pol, 2024, 80(12): 803–815