Antibiotic resistance has grown at an alarming rate over the last few decades. To prevent a post-antibiotic era in which common infections could become lethal, an estimated 20 novel families of antibiotics must be developed in the next 50 years. Political groups in both the U.S. and Europe are each working to promote new development, but there are concerns the results may not come in time.
NoonAntibiotic resistance has grown at an alarming rate over the past few decades. The situation is now described as “urgent” by the World Health Organization (WHO). Resistance occurs naturally in bacteria as a result of environmental pressures and horizontal gene transfer, but it has been hastened by the widespread misuse of antibiotics. Several bacterial species are now immune to numerous families of antibiotics, including methicillin-resistant Staphylococcus aureus and tuberculosis, as has been widely reported in the media.
To prevent the arrival of a postantibiotic era in which common infections can once again kill, it is estimated that 20 novel families of antibiotics must be developed within the next 50 years.1 Antibiotic development is difficult, however, with only 12 new drugs approved by FDA or the European Medicines Agency since 2000, of which only 4 boast first-in-class status. The arrival of the genomic era in the 1990s revealed a plethora of conserved bacterial genes that lacked equivalents in mammalian cells and that on validation via knockout, mutational, or induced-gene experiments presented ideal targets for antibiotic development.2 Up to 350 potential targets were identified in this and similar studies by pharmaceutical companies. Despite this wide range of validated essential genes, however, researchers at GlaxoSmithKline identified only 16 chemical inhibitors with potential antibiotic activity during 6 years of both whole-cell and target-based (virtual and assayed) screening against the purified proteins of 67 genes, with only 1 progressing to human trials.3 Similar results were reported across the industry. These high failure rates, coupled with the short courses for which antibiotics are prescribed, mean that financial returns on antibiotic development are very poor, with many pharma companies having left the field.
In response to growing concerns over the lack of new antibiotics, the United States Congress passed the 2011 Generating Antibiotics Incentives Now (GAIN) Act to help boost development in the field. This was followed by Europe’s similarly aimed Combatting Bacterial Resistance in Europe (COMBACTE) project that was initiated in January 2013. These projects aim to improve antibiotic development through incentives, such as priority FDA reviews, an additional 5 years of market exclusivity, changes to clinical trial regulations, and the establishment of cross-country clinical trial networks to improve patient recruitment.4
Unfortunately, it appears that these incentives have done little to promote novel antibiotic development. GBI Research’s report product Frontier Pharma aims to identify first-in-class targets from the company’s extensive proprietary databases. Our research has identified that although the antibiotics pipeline is vast, with 741 products currently in development, only 75 drugs are first-in-class, acting on 38 targets. The pipeline is predominantly generic and me-too drugs. Diversity among these first-in-class drugs is limited, with the majority being novel protein synthesis inhibitors and bacterial cell wall disruptors-mechanisms of action that are well established among marketed drugs. Given their essentiality in bacterial survival, drugs against these targets are likely to be broad spectrum but to present the same risk of resistance as marketed antibiotics. Antivirulence inhibitors, which represent a more novel approach, account for 17 first-in-class targets. Bacterial virulence factors include proteins essential in host cell adhesion (such as bacterial adhesins), regulators and molecular components essential in protein secretion, molecules involved in quorum sensing (cell–cell communication) and the formation of biofilms, as well as the production and secretion of bacterial toxins. It is speculated that this approach would prevent the disease-causing symptoms of bacterial infection while relying heavily on the host’s innate immune system to clear infection. Although further studies are needed to prove this theory, it is hoped that this mode of action would reduce selection for antibiotic-resistant clones.
NEXT: "The dynamics of antibiotic use not expected to alter significantly over the next few years"
Improvements to research methodologies have been suggested to increase the success of identifying first-in-class compounds. One recommendation is to revise the criteria used to isolate lead compounds (Lipinski’s rule of five), which typically apply to drug effects in mammalian cells, the rules of which bacteria generally do not observe.5 Alternatively, the desire to find a broad-spectrum antibiotic, which typically acts against conserved genes, may ultimately be hindering successful antibiotic development. Although a less attractive option commercially, identifying a chemical inhibitor of a molecular target essential for cell viability and/or disease progression in a single bacterial species may represent a viable prospect if that infection is particularly common or if it has developed a high degree of resistance to available therapies.
Even if these changes are successfully implemented and significant numbers of lead compounds are brought to human trials, the desire to restrict the spread of resistant disease means that it is unlikely that any first-in-class antibiotic would be widely used. Prescription would instead be restricted to severe cases of multidrug-resistant disease. Furthermore, with the United Kingdom’s National Institute for Clinical Excellence requiring strong drug efficacy-to-cost ratios in order to recommend a novel antibiotic’s widespread prescription, it is unlikely that a novel antibiotic, with its necessary premium price, would be able to compete with the wide range of low-cost generic antibiotics over the short term in the absence of overwhelming clinical trial results.
As a result of the lack of innovation, the desire to maintain bacterial susceptibility to new antibiotics, and the premium cost of any newly approved therapies, the dynamics of antibiotic use are not expected to alter significantly over the next few years. The use of generics will continue, with the generic and me-too drugs that dominate the pipeline simply adding to the number available. As antibiotic resistance increases over the coming few years, it can be speculated that an increasing number of more expensive, second-line antibiotics will have to be utilized, such as the use of kanamycin and streptomycin in multidrug-resistant tuberculosis. Ultimately, the limited number of newly approved novel antibiotics will have a minimal impact on the treatment algorithms for bacterial infections.
Novel antibiotics will prove essential as resistance increases in the long term; however, such little success in this field coupled with the fact that antibiotic development remains an unprofitable venture for pharma companies means that sufficient novel antibiotic development may be too little too late. The already implemented regulatory incentives for antibiotic development may be partially successful at stimulating some interest in the field, but ultimately, new commercial models to make antibiotic development profitable are desperately needed. One approach, as proposed by WHO, is to uncouple a drug’s sales cost from its developmental cost. Others have proposed increasing public funding or introducing purchaser contracts to ensure the sale of a novel antibiotic for an appropriate timeframe. The successful implementation of these recommendations remains to be seen.
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Ms Noon is a senior analyst for GBI Research, based in the United Kingdom. Her research interests include personalized medicine specializing in cancer therapies, and drug discovery and development. She holds a BSc Hons in Cell Biology from Durham University, Durham, England.