The birth of penicillin in 1943 opened the golden age of antimicrobial therapy. However, after the 1980s, large pharmaceutical companies faced major scientific challenges in finding new antibiotics to solve antimicrobial resistance. Coupled with the inability to guarantee the continued growth of the market and profits in this field, the development of antibacterial drugs was gradually abandoned.
Exploring the development status of pre-clinical antibacterial product pipelines, you can see the future development direction of antibacterial drugs: 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 antipathogenic drugs, 29 antibodies and antibody-drug Eurolinks, 27 antibacterial vaccines，32 synergists to enhance another existing antibiotic drug, 21 microbial modulating drugs, 15 old drugs, new uses (such as non-antibiotics or antibiotic combinations), 12 immunomodulators and 18 other projects (for example, nano antibiotic). Almost 40% of projects focus on methods that target pathogens, which is unprecedented in the history of antibiotics.
1. Direct antibacterial drugs
Among the 187 traditional antibacterial drugs that directly inhibit or kill bacteria, most 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;
Other new targets include bacterial ribosomes, membranes, cell walls, transcription and/or translation, gene interference and new binding sites in metabolism. The other 17 items (9%) could not be classified due to insufficient information.
2. Synergists
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 in 32 preclinical projects. β-Lactamase inhibitors (β-Lactamaseinhibitors) are a new class of β-lactam drugs. Plasmid delivery produces β-lactamase, which causes the β-lactam ring of some drugs to be hydrolyzed and inactivated. This is the main way for pathogens to resist some common β-lactam antibiotics (penicillins, cephalosporins). It is worth noting that there are currently no approved inhibitors including metallo-beta-lactamases. The 12 items are 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 R&D pipeline can expand the antibacterial spectrum (for example, from anti-Gram-positive drugs to Gram-negative activities), enhance activity, restore the activity against bacteria or prevent the nephrotoxicity of nephrotoxic antibiotics such as colistin or aminoglycoside.
3. Old drugs, new uses
The 15 new-use drugs refer to drugs that have been approved for use in other disease fields or antibacterial drugs that have not been tested before or have not been used for specific purposes. Such drugs can be developed through combination or developed into different new preparations. Based on the understanding of existing knowledge, development time and cost 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
Phage is a general term for viruses that infect microorganisms such as bacteria, fungi, algae, actinomycetes or spirochetes, and some of them can cause the lysis of host bacteria. Phage growth and reproduction in host cells can cause the lysis of pathogenic bacteria, reduce the density of pathogenic bacteria, thereby reducing or avoiding the chance of infection or disease of pathogenic bacteria, and achieving the purpose of treating and preventing diseases, that is, phage therapy. Currently 27 institutions are developing 33 phage or phage-derived therapies. Phage therapy may include natural phage cocktails (11 items), engineered phage cocktails (11 items, 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 lysosin for Gram-negative bacteria. Phage therapy is species-specific, so the most common targets for this method are Pseudomonas aeruginosa and Staphylococcus aureus, but phage therapy for Clostridium difficile and many other pathogen infections are also under development.
5. Microbiota modulation 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. Finch Therapeutics, a cutting-edge microbiome, announced that its full-spectrum microbial product CP101 for the treatment of recurrent Clostridium difficile infections (rCDI) has been awarded a breakthrough therapy designation by the FDA. Few target the lung, sinus, or skin microbiota.
6. Anti-pathogenic drugs
Anti-pathogenic 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, multiple adjustments and persistence. Anti-pathogenic drugs need to be used in combination with direct-acting antibacterial drugs, so they are generally designed as adjuvant therapies. Most projects specifically target Pseudomonas aeruginosa, Staphylococcus aureus and Clostridium difficile.
7. Antibodies and antibody drug conjugates
Of the 29 antibodies (including antibody-drug conjugates), most of them have been developed as preventive or adjuvant therapies for Staphylococcus aureus infections, followed by infections of Clostridium difficile and Pseudomonas aeruginosa, each with more than 3 items. There are almost no antibodies against Acinetobacter, Escherichia coli and other bacteria. Eleven of these antibody projects are already in the pre-clinical and late stages of development.
8. Vaccine
Of the 27 vaccine programs, 5 are against Staphylococcus aureus. Less than 5 items are for Pseudomonas aeruginosa, Acinetobacter, Klebsiella pneumoniae, Neisseria gonorrhoeae and Salmonella nontyphi. Several other projects focus on a single rare pathogen. There are also multi-antigen and/or multivalent vaccines against bacterial populations.
9. Other projects
The other 18 items include nanoparticles with antibacterial functions. Nanoparticles and synthetic polymers are 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 immunomodulators that support the elimination of pathogens by regulating the immune system.
In short, compared with antibacterial drugs currently on the market or in clinical development, the preclinical development pipeline is diversified and innovative. Although these projects may not completely solve the existing problem of antibiotic resistance, this innovation may mean the current desire for new therapies and the direction of the antibacterial drug market in the future.