Inspiration

Nothing in pipeline? - The problem of modern antibiotic research

Worldwide globalisation and a rising world population creates a new problem for our society: Pathogens acquire mutations and different resistance factors leaving us with less and less effective antimicrobials. The World Health Organisation (WHO) considers the most problematic organisms to be multi-resistant Mycobacterium tuberculosis, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and many others (Geneva: World Health Organization 2017).

Besides fighting antibiotic misuse by raising awareness and health education to decrease the number of new resistant bacteria, there is a necessity for new antibacterial substances and therapies. This lies within the responsibility of universities and companies. In contrast, every year, the FDA approves less and less new antibacterial compounds. This is due to the fact, that research in the field of new antibiotics for pharmaceutical companies is not attractive: New substances are usually only used as reserve antibiotics for patients suffering from infections with highly resistant pathogens and therefore provides in its patented period only a low budget income.

Most new antibiotic substances are found in new bacterial strains, while (bio-)chemically modified compounds are rather rare. At the same time, it gets harder to identify new potent candidates. We need new strategies to produce effective compounds that are specifically engineered to fight resistant pathogens and new methods to achieve these modifications. This is where antibiotic classes, that provide potency in theory, but fail in compliance and practical application, come into play.

Introducing the aminocoumarins: potent antibiotics with little relevance in clinical therapy

Aminocoumarins are one of many substance classes with almost no use in the antibacterial therapy. So far, three aminocoumarins are known: Novobiocin, Clorobiocin and Coumermycin A1. (Heide 2014) Furthermore, the structurally different Simocyclinone D8 has been described as a fourth aminocoumarin (Schimana et al. 2000).

All aminocoumarins produced by different streptomyces species have an aminocoumarin (Figure 3 green) and a deoxyribose (Figure 3 blue) moiety in common. Aminocoumarins irreversibly bind to and inhibit the B subunit of the bacterial gyrase and therefore prevent the cell from successful mitosis (Lawson and Stevenson 2012). The human topoisomerase II is a known off-target, which can cause toxicity when highly dosed. Resistances are mediated by unspecific multidrug exporters (MDR) or mutations in the gyrase binding pockets. The latter are only found in aminocoumarin producing Streptomyces strains or bacteria that were forced to mutate by selection under low dose aminocoumarin application (Fujimoto-Nakamura et al. 2005).
Disadvantages that prevent aminocoumarins from more frequent clinical use include path of administration (i.v. only), a narrow efficacy spectrum (no gram-negative bacteria are affected), unfavorable pharmacokinetics caused by a low water solubility or irritations at the injection spot caused by toxicity due to a slow drug distribution in the blood (Grayson et al 2010). So far, Novobiocin is the only aminocoumarin approved by the FDA for antibiotic therapy. Lately, studies have found beneficial results for cancer therapies with topoisomerase II inhibitors in combination with Novobiocin.