Antibacterial Therapy - BiopharmaDirect

Antibacterial Therapy

The birth of penicillin in 1943 opened the golden era of antibacterial therapy. However, after the 1980s, large pharmaceutical companies faced major scientific challenges in finding new antibiotics to solve antimicrobial resistance, and there was no guarantee for continuous market and profit growth in this field, so the development of antibacterial drugs began to stagnate.

Overview of pre-clinical antibacterial product pipelines

It is reported that 314 institutions are currently developing 407 preclinical antibacterial drug projects, of which small and medium-sized companies account for 81%, while large companies account for only 4%. In terms of categories, it includes 187 direct antibacterial drugs, 33 bacteriophage or phage-derived peptides, 33 anti-pathogenic drugs, 29 antibodies and conjugated antibody drugs, 27 antibacterial vaccines, and many other projects (for example, nano antibiotics). Almost 40% of the projects focus on methods that target pathogens, which is unprecedented in the history of antibiotics.

Figure 1. Overview of the preclinical antibacterial pipeline. (Ursula Theuretzbacher, et. Al. 2019)

1. Direct antibacterial drugs

Among the 187 traditional antibacterial drugs that directly inhibit or kill bacteria, most of them are synthetic or natural small molecule chemical drugs, which are mainly divided into three categories: improved derivatives of known antibiotics (old targets), new chemical drugs with new targets, and unknown or uncertain drugs with unknown targets. Among them, 35 old targets (accounting for 19% of this category) include β-lactams and other penicillin binding protein inhibitors, fluoroquinolones and new bacterial topoisomerase inhibitors, aminoglycosides, and polymyxins and macrolides. 135 new targets (72%) include synthetic and natural antimicrobial peptides (AMP), natural products and deacetylase (LpxC) inhibitors, bacterial ribosomes, membranes, cell walls, transcription and/or translation or even new binding sites in gene interference and metabolism. The other 17 items (9%) could not be classified due to insufficient information.

2. Synergist

Synergists are drugs that have no antibacterial activity but can transform, restore or enhance the activity of another antibiotic, such as β-lactamase inhibitors. Currently there are 32 preclinical projects, and among them, 12 projects are working on the inhibition of β-lactamase, including metallo-β-lactamase. Despite extensive research, so far, various bacterial efflux pump inhibitors have not been clinically developed. The enhancer project includes 5 efflux inhibitors for different efflux pumps. Other enhancers in the pre-clinical research and development pipeline can expand the antibacterial spectrum, enhance activity, restore activity against bacteria or prevent the nephrotoxicity of other nephrotoxic antibiotics such as colistin or aminoglycosides.

3. New uses for drugs

The old drugs can be approved for use in other disease fields or antibacterial drugs that have not been previously tested or used for specific purposes. Such drugs are developed through combination or developed into different new preparations. Based on the understanding of the existing drugs, time and cost needed for developing their second medical use can be reduced. However, the value of this type of drug development method in the clinical environment has yet to be proven.

4. Phage and phage-derived peptides

Currently 27 institutions are developing 33 phage or phage-derived therapies. Phage therapy may include natural phage cocktails, engineered phage cocktails (partly CRISPR enhanced) and other highly diverse scientific methods. The most common phage product is phage endolysin for Staphylococcus aureus, while there are relatively few projects for recombinant lysin against Gram-negative bacteria. Phage therapy is species-specific, so the most common targets of this method are Pseudomonas aeruginosa and Staphylococcus aureus, but phage therapy for Clostridium difficile and many other pathogen infections is also under development.

5. Microbiota regulation therapy

There are 21 different microbial regulation therapies currently being developed preclinically. The most common strategy is modified probiotics with enhanced functional properties. Other items are natural strains derived from the natural microbial community, which have a variety of potential beneficial effects. Pre-clinical projects are also pursuing inactivators of antibiotics in the intestines and absorbents of bacterial toxins. Most microbial modulation therapies in preclinical development target the gut microbiota, especially Clostridium difficile, while only few target the lung, sinus, or skin microbiota.

6. Anti-pathogenic drugs

Antipathogenic drugs do not directly inhibit or kill bacteria but affect a wide range of virulence factors of bacteria. 33 antipathogenic drug projects are adopting multiple strategies, including inhibition of bacterial quorum sensing, biofilm formation, adhesion, and multiple regulation and persistence. Anti-pathogenic drugs need to be used in combination with direct-acting antibacterial drugs, so they are generally designed as adjuvant therapy. Most projects specifically target Pseudomonas aeruginosa, Staphylococcus aureus and Clostridium difficile.

7. Antibodies and antibody drugs conjugates

Of the 29 antibodies (including antibody-drug conjugates), most of the antibodies were developed as preventive or adjuvant therapy for Staphylococcus aureus infections, followed by C. difficile and Pseudomonas aeruginosa infections, each with more than 3 projects being carried out. There are almost no antibodies against Acinetobacter, E. coli and other bacteria. Eleven of these antibody projects are already in the pre-clinical and clinical stages of development.

8. Vaccine

Of the 27 vaccine programs, 5 are against Staphylococcus aureus. Less than 5 projects are for Pseudomonas aeruginosa, Acinetobacter, Klebsiella pneumoniae, Neisseria gonorrhoeae and Salmonella non-typhi. Several other projects all focus on a single rare pathogen. There are also multi-antigen and/or multivalent vaccines against bacterial populations.

9. Other projects

Among all the pre-clinical antibacterial product pipelines, 18 projects explore nanoparticles with antibacterial properties. Nanoparticles and synthetic polymers are the carriers used to deliver drugs, while nano-antibiotics can directly kill microorganisms by generating reactive oxygen species, permeating cell membranes, triggering DNA damage or interrupting electron transport across the membrane. In addition, there are 12 projects researching on immunomodulators that regulate the immune system to support the elimination of pathogens.

In short, compared with antibacterial drugs currently on the market or in clinical development, the preclinical development pipeline is diverse and innovative. Although these projects may not completely solve the existing problem of antibiotic resistance, the innovation may point a way for future direction of the antibacterial drug market.