Meeting with resistance

Bacteria are challenging healthcare resources worldwide through their increasing resistance to antibiotics. Bacterial resistance has become a major threat to public health, as acknowledged by the World Health Organisation and the European Society for Clinical Microbiology and Infectious Diseases. The organisms reproduce rapidly, exist in vast numbers and exchange resistance genes with great efficiency. The phenomenon of bacterial resistance existed long before the clinical use of antibiotics, as bacteria naturally produce toxins (antibiotics) with which to attack other micro-organisms (including other bacterial species) and the targeted micro-organisms respond by developing resistance to these toxins.

The decreasing number of new antibiotics approved for clinical use has weakened the resources available to treat resistant infections. Strategies to counter bacterial resistance include surveillance of resistance coupled with improved infection control and optimal use of antibiotics (such as prescribing for the shortest period possible). However, the most that such measures can achieve is to stabilise resistance; the evidence is that resistance will continue to have a high prevalence. The loss of efficacy of the current arsenal of antibiotics shows that there is a pressing need for new and effective antibacterial compounds.

Introducing lantibiotics
Lantibiotics (or lanthionine-containing antibiotics) have no known candidate resistance mechanisms and have not yet been used clinically to treat bacterial infections. The first example, nisin, was discovered in 1928. They are polypeptides that contain unusual amino acids such as lanthionine and ß-methyllanthionine, which are thought to increase structural stability and promote biological activity.

Lantibiotics are produced by, and mainly act on, Gram-positive bacteria. The two major classes of lantibiotics bind to the same molecular target, the bacterial cell wall precursor molecule lipid II, but with different resulting mechanisms of microbial killing. Type A lantibiotics (with flexible, elongated structures) form pores in the cytoplasmic membrane and type B lantibiotics (with a rigid, globular shape) inhibit cell wall biosynthesis. Nisin, a type A lantibiotic that both disrupts cell wall biosynthesis and promotes pore formation, has been used as a non-toxic food preservative for decades and kills bacteria effectively at nanomolar concentrations. The success of this compound has triggered interest in the therapeutic potential of lantibiotics.

The principal reason for the decades-long delay in bringing lantibiotics into clinical use is manufacturing difficulties. Historically, the fermentation methods required to produce natural lantibiotics have not provided sufficient, cost-effective quantities for clinical testing and commercialisation, and organic synthesis schemes have not, until recently, produced a completely functional lantibiotic.

Several pharmaceutical companies appear to have recently found ways of overcoming the manufacturing obstacles. For example, the lantibiotic lancovutide, manufactured by fermentation methods, is in clinical trials with AOP Orphan Pharmaceuticals for non-infectious indications (cystic fibrosis and dry eye syndrome). Other companies are preparing to bring lantibiotic-based agents into clinical development for the treatment of bacterial infections. Two such compounds are being developed for the treatment of resistant Gram-positive infections and another is being developed for the relatively narrow indication of Clostridium difficile infection.  

The lantibiotic pipeline
MU1140-S, a synthetic analogue of the lantibiotic MU1140, is being developed in late preclinical trials by US company Oragenics. MU1140 is produced naturally by Oragenics' proprietary strain of Streptococcus mutans and has shown bactericidal activity against a wide range of Gram-positive bacteria. The company claims that it has overcome the historical manufacturing difficulties of lantibiotics by application of its Differentially Protected Orthogonal Lantionine Technology (DPOLTTM); the successful synthesis of MU1140-S by means of this technology was reported in October 2008. Oragenics believes that large-scale, cost-effective production of clinical grade MU1140-S will be possible by use of DPOLTTM.

The company reported in late 2010 that it expected to complete preclinical trials of MU1140-S during the first half of 2011, with the filing of an investigational new drug application with the US FDA (for regulatory permission to conduct clinical trials) scheduled for mid-2011. The most likely potential application of the drug appears to be the treatment of multi-drug-resistant, hospital-acquired Gram-positive infections. It will be administered by slow intravenous infusion in order to maximise therapeutic effect and minimise the risk of hypersensitivity reactions.

The lantibiotic NAI-107 is being developed by a US company, Sentinella Pharmaceuticals, as an injectable therapy for multi-drug-resistant Gram-positive infections. Sentinella acquired the rights to the compound from the Italian companies NAICONS and NexThera Biosciences in January 2010. The drug, which is prepared by a fermentation process, has proven effective in animal models of infection with multi-drug-resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus. It is not clear how Sentinella plans to overcome the manufacturing difficulties associated with the fermentation process, and no estimated date for clinical trial initiation is available. It appears unlikely that NAI-107 is as far advanced in development as Oragenics' MU1140-S.

NVB302 is a lantibiotic that is being developed by the UK company Novacta for the treatment of hospital-acquired C. difficile infections. These gastrointestinal infections can range from mild diarrhoea to life-threatening colitis. NVB302 has shown similar efficacy to vancomycin in an animal model of C. difficile infection and has demonstrated selective in vitro killing of C. difficile versus other normal gut flora. Manufacturing of this compound by current Good Manufacturing Practice standards, using fermentation processes, began in June 2010; this product will be used initially for the remaining preclinical trials and also for phase I clinical trials. The likely date of clinical trial initiation is unclear.

Novacta is working with DSM BioSolutions for manufacture of NVB302 because of DSM's expertise in scaling up fermentation processes for antibacterial agents from actinomycetes. In addition to its C. difficile programme, Novacta has other lantibiotics programmes for bacterial infections at a less advanced development stage. The company plans to treat resistant, hospital-acquired Gram-positive infections and hospital-acquired Gram-negative infections with lantibiotics.

The future of lantibiotics in the therapy of bacterial infections looks promising. With the most advanced compound, Oragenics' MU1140-S, likely to enter clinical trials later this year, help is on the way for clinicians battling multi-drug-resistant Gram-positive infections in hospitalised patients. In addition, Novacta's NVB302 for the treatment of hospital-acquired C. difficile infection has the potential to be a useful therapy for this serious infection.

Drug launches

The Author
Pipeline was written by Philip Hair of Adis International (Wolters Kluwer Health Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought. For information on Adis services, contact Kuljeet Sohanpal on +44 (0)207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com

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