Antimicrobial resistance (AMR) is a major global health issue when microorganisms like bacteria and fungi evolve to resist the effects of drugs designed to kill them. The World Health Organization (WHO) identifies AMR as one of the top 10 global public health threats.

Since the 1980s, the development of new antibiotics has stagnated, leading to an over-reliance on older drugs. Bacteria have evolved various resistance mechanisms, including reducing membrane permeability, using efflux pumps, producing enzymes that degrade antibiotics, modifying antibiotic targets, and forming protective biofilms.

These adaptations significantly reduce the effectiveness of nearly all known antibiotics, complicating the fight against bacterial infections.

Since 2010, 29 antibiotics have received marketing authorization; most of these are modifications to existing classes, such as carbapenems, aminoglycosides, and macrolides.

The WHO AWaRe (Access, Watch, Reserve) antibiotic book provides concise, evidence-based guidance on the choice of antibiotic, dose, route of administration, and duration of treatment for more than 30 of the most common clinical infections in children and adults in both primary health care and hospital settings.

It emphasizes a need to move beyond traditional antibiotic therapies by exploring alternative treatments like antimicrobial peptides, bacteriophages, monoclonal antibodies, and gene therapies. Artificial intelligence (AI) is vital in speeding up antibiotic susceptibility testing, improving large-scale AMR surveillance, and accelerating drug discovery.

Also read Halicin: AI-Powered Revolution in Antibiotic Discovery

List of Non-Antibiotic Therapies and treatments validated with clinical trials

New-generation antibiotics

Sulbactam-durlobactam combines two drugs to combat antibiotic-resistant bacterial infections, particularly infections caused by carbapenem-resistant Acinetobacter baumannii. It is designed to inhibit the bacterial enzymes that lead to antibiotic resistance and enhance the effectiveness of β-lactam antibiotics.

Gepotidacin inhibits two bacterial enzymes, DNA gyrase and topoisomerase IV, essential for bacterial DNA replication, transcription, and repair. Because of this, it can target bacteria that have developed resistance to other commonly used antibiotics, such as fluoroquinolones.

Zoliflodacin inhibits bacterial DNA synthesis by targeting DNA gyrase (GyrB subunit), a key enzyme necessary for bacterial DNA replication and transcription. This distinguishes it from older antibiotics, like fluoroquinolones, which also target DNA replication but interact with different parts of the enzyme. This is particularly potent against Neisseria gonorrhoeae, including strains resistant to current treatments like ceftriaxone and azithromycin.

Human monoclonal antibodies

Obiltoxaximab is a monoclonal antibody used as a treatment and preventive therapy for inhalational anthrax caused by Bacillus anthracis. It works by binding to the protective antigen (PA) component of anthrax toxins, preventing the toxin from entering cells and exerting its harmful effects. It was approved by the U.S. FDA in 2016.

Tosatoxumab (AR-301) is a humanized monoclonal antibody that targets Staphylococcus aureus, including drug-resistant strains like MRSA (methicillin-resistant Staphylococcus aureus). It works by binding to clumping factor A (ClfA), a surface protein on the bacteria, preventing it from adhering to host tissues and evading the immune system.

Suvratoxumab is a monoclonal antibody designed to target Staphylococcus aureus infections, particularly in patients at high risk of developing pneumonia, including ventilator-associated pneumonia (VAP). It works by binding to the alpha-toxin produced by Staphylococcus aureus, neutralizing its toxic effects and preventing lung tissue damage.

Bezlotoxumab is a monoclonal antibody used to prevent the recurrence of Clostridioides difficile (C. difficile) infection (CDI), particularly in patients at high risk for recurrent infections. It works by neutralizing toxin B, one of the critical toxins produced by C. difficile, which is responsible for the damage to the intestinal lining and inflammation during infection.

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Antimicrobial peptides

LL-37 is an antimicrobial peptide of 37 amino acids belonging to the cathelicidin family, naturally produced in humans. It exhibits broad-spectrum antimicrobial activity against various pathogens, including both Gram-positive and Gram-negative bacteria, fungi, and some viruses, primarily by disrupting microbial membranes

Omiganan is a synthetic antimicrobial peptide effective against various pathogens, including Gram-positive and Gram-negative bacteria. It disrupts bacterial cell membranes, leading to cell lysis and death. With broad-spectrum activity against pathogens like Staphylococcus aureus (including MRSA) and Pseudomonas aeruginosa, omiganan is being explored for topical applications to prevent infections in wounds and surgical sites.

Dalbavancin is a novel lipoglycopeptide antibiotic primarily used to treat gram-positive severe bacterial infections, including those caused by Staphylococcus aureus (including MRSA) and Streptococcus species. Dalbavancin works by inhibiting bacterial cell wall synthesis, specifically binding to the D-alanyl-D-alanine terminus of peptidoglycan precursors, which is crucial for bacterial cell wall integrity.

Orbactiv is a lipoglycopeptide antibiotic used primarily to treat acute bacterial skin and skin structure infections (ABSSSI) caused by Gram-positive bacteria, including Staphylococcus aureus (including MRSA) and Streptococcus species. It inhibits bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminus of peptidoglycan precursors, similar to other glycopeptides, but it also disrupts membrane integrity, enhancing its antibacterial activity.

Pexiganan a novel antimicrobial peptide that is being developed as a topical treatment for infected diabetic foot ulcers and other skin infections. It is derived from the natural antimicrobial peptide magainin and exhibits broad-spectrum activity against a variety of Gram-positive and Gram-negative bacteria. It disrupts bacterial cell membranes through its amphipathic structure, leading to cell lysis and death.

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Bacteriophages

S aureus phage based phase IIa randomized trial was done to evaluate bacteriophage therapy in patients with diabetic foot osteomyelitis. NCT05177107

Pyobacteriophages type of bacteriophage specifically designed to target and infect pyogenic bacteria, which are bacteria that produce pus and cause infections, such as Staphylococcus aureus, Streptococcus pyogenes, and Pseudomonas aeruginosa. NCT03140085

P aeruginosa phage based bacteriophage therapy is used in a clinical trail for E. coli or P. aeruginosa wound infections in burned patients NCT02116010

Gene therapy

CRISPR: It’s a CRISPR-Cas9 gene-editing technology used to modify genes in order to treat or prevent diseases. CRISPR-Cas9 works by utilizing a guide RNA that directs the Cas9 enzyme to a specific location in the genome where it can create a double-strand break in the DNA. The cell's natural repair mechanisms then kick in, allowing scientists to either disable a faulty gene or insert a new segment of DNA.

A detailed review is published in The Lancet Microbe.