The Expanding Arsenal Against Antimicrobial Resistance

As antimicrobial resistance (AMR) threatens millions of lives annually, researchers are mapping an expanding pipeline of novel drugs, biological therapies and technology-driven solutions that could redefine how infectious diseases are treated.

Global Burden and the One Health Approach

Antimicrobial resistance is a significant global public health concern, impacting communities and healthcare settings worldwide. A 2016 report estimated that approximately 10 million deaths could occur annually by 2050 due to AMR [1]. Strategies to combat AMR are being devised at local, national, and international levels, utilizing a multidisciplinary “One Health” approach. This includes surveillance, antimicrobial stewardship, infection prevention measures, and therapeutic innovation [1].

Recently Approved Antibacterial Drugs

Over the past decade, a limited number of novel antibacterial agents have been introduced: 20 antibiotics, four non-traditional antibacterial drugs, and seven beta-lactam/beta-lactamase combinations [2]. Many of these drugs are derivatives of existing antibiotic classes and may be susceptible to similar resistance mechanisms.

Two recently approved first-in-class antibiotics include:

• Lefamulin: Approved by the Food and Drug Administration (FDA) in 2019 for the treatment of community-acquired bacterial pneumonia. It works by blocking protein synthesis [2].
• Gepotidacin: Approved in 2025 for the treatment of uncomplicated urinary tract infections in females and adolescents. It inhibits bacterial DNA replication [2].

Additional approvals include:

• Emblaveo (aztreonam/avibactam): Approved in 2025 to treat complicated intra-abdominal infections, hospital-acquired pneumonia, ventilator-associated pneumonia, complicated urinary tract infections, and aerobic gram-negative infections [2]. It received marketing authorisation from the European Medicines Agency in 2024.
• Xacduro (sulbactam/durlobactam): Approved to treat infections caused by Acinetobacter baumannii-calcoaceticus complex [2].

Novel Therapeutic Approaches

Antimicrobial Peptides and Oligonucleotide Therapies

Antimicrobial peptides (AMPs), natural components of innate defenses, are receiving attention for their antimicrobial properties and potential to modulate immune responses. Of over 3,000 AMPs discovered, only seven, all originating from soil bacteria, have been approved [2].

Zosurabalpin, a novel peptide targeting Acinetobacter baumannii, is entering phase 3 clinical trials. It blocks lipopolysaccharide transport and is expected to be unaffected by current resistance mechanisms [2]. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) have demonstrated antibacterial and antibiofilm activity in animal models against Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, and Klebsiella pneumoniae [2].

Natural Sources of Antimicrobial Agents

Honey, particularly Manuka honey, has a history of use in wound infections and is being researched for its effects against antibiotic-resistant pathogens. Its antibacterial properties are attributed to its physicochemical characteristics and components like hydrogen peroxide and methylglyoxal [2]. Honeybee venom and spider venoms have likewise shown antibacterial effects against multidrug-resistant pathogens [2].

Microbiome-Based Therapies

Rebyota, a live fecal microbiota-based biotherapeutic, was approved in 2022 for recurrent Clostridioides difficile infection (CDI). Vowst, the first oral fecal microbiota therapy, was approved in 2023 [2]. Fecal microbiota transplantation (FMT) shows efficacy in decolonizing and eliminating carriage of multidrug-resistant bacteria and antibiotic resistance genes.

Predatory Bacteria

Predatory bacteria, like Bdellovibrio bacteriovorus, can kill other bacteria without inducing inflammation. Resistance to these bacteria appears unlikely due to their prey recognition and destructive mechanisms [2]. Micavibrio aeruginosavorus and B. Bacteriovorus have shown promise in animal models.

Future Directions

The rise in antibiotic resistance necessitates continued research and development of novel therapeutic strategies. Many approaches are still in preclinical or early clinical stages. Continued funding and interdisciplinary collaboration are crucial for translating these innovations into clinical care [2].