Strategies for the Discovery and Development of New Antibiotics from Natural Products: Three Case Studies.

Natural products continue to be a predominant source for new anti-infective agents. Research at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the Helmholtz Centre for Infection Research (HZI) is dedicated to the development of new lead structures against infectious diseases and, in particular, new antibiotics against hard-to-treat and multidrug-resistant bacterial pathogens. In this chapter, we introduce some of the concepts currently being employed in the field of antibiotic discovery. In particular, we will exemplarily illustrate three approaches: (1) Current sources for novel compounds are mainly soil-dwelling bacteria. In the course of our antimicrobial discovery program, a biodiverse collection of myxobacterial strains has been established and screened for antibiotic activities. Based on this effort, one successful example is presented in this chapter: Antibacterial cystobactamids were discovered and their molecular target, the DNA gyrase, was identified soon after the analysis of myxobacterial self-resistance making use of the information found in the respective biosynthesis gene cluster. (2) Besides our focus on novel natural products, we also apply strategies to further develop either neglected drugs or widely used antibiotics for which development of resistance in the clinical setting is an issue: Antimycobacterial griselimycins were first described in the 1960s but their development and use in tuberculosis therapy was not further pursued. We show how a griselimycin derivative with improved pharmacokinetic properties and enhanced potency against Mycobacterium tuberculosis revealed and validated a novel target for antibacterial therapy, the DNA sliding clamp. (3) In a third approach, biosynthetic engineering was used to modify and optimize natural products regarding their pharmaceutical properties and their production scale: The atypical tetracycline chelocardin is a natural product scaffold that was modified to yield a more potent derivative exhibiting activity against multidrug-resistant pathogens. This was achieved by genetic engineering of the producer strain and the resulting compound is now subject to further optimization by medicinal chemistry approaches.

Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins.

The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.