Abstract
The global threat of multiresistant pathogens has to be answered by the development of novel antibiotics. Established antibiotic applications are often based on so-called secondary or specialized metabolites (SMs), identified in large screening approaches. To continue this successful strategy, new sources for bioactive compounds are required, such as the bacterial genera Xenorhabdus or Photorhabdus. In these strains, fabclavines are widely distributed SMs with a broad-spectrum bioactivity. Fabclavines are hybrid SMs derived from nonribosomal peptide synthetases (NRPS), polyunsaturated fatty acid (PUFA), and polyketide synthases (PKS). Selected Xenorhabdus and Photorhabdus mutant strains were generated applying a chemically inducible promoter in front of the suggested fabclavine (fcl) biosynthesis gene cluster (BGC), followed by the analysis of the occurring fabclavines. Subsequently, known and unknown derivatives were identified and confirmed by MALDI–MS and MALDI–MS2 experiments in combination with an optimized sample preparation. This led to a total number of 22 novel fabclavine derivatives in eight strains, increasing the overall number of fabclavines to 32. Together with the identification of fabclavines as major antibiotics in several entomopathogenic strains, our work lays the foundation for the rapid fabclavine identification and dereplication as the basis for future work of this widespread and bioactive SM class.
Highlights
The constantly increasing threat of multiresistant pathogens requires the development of new antibiotics, as they are indispensable to maintain the state of health of our society [1]
Biosynthetic gene clusters for the fabclavine production are highly conserved During the screening for homologous fcl biosynthesis gene cluster (BGC) in Xenorhabdus and Photorhabdus strains, several candidate clusters were identified, which were conserved both in their BGC synteny as well as at the single protein level (Figure 2) [22]
This study revealed a large chemical diversity for fabclavine derivatives among different Xenorhabdus strains, which is achieved by the promiscuity of single enzymes or domains during the biosynthesis
Summary
The constantly increasing threat of multiresistant pathogens requires the development of new antibiotics, as they are indispensable to maintain the state of health of our society [1]. Research in the field of novel SMs with antimicrobial activity is vital to provide new avenues to new antiinfective drugs or lead compounds
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