Abstract: Antibiotic resistance development is continuously eroding our anti-infective treatment options and in spite of considerable investment in academia and industry sectors, we are not very successful in bringing new drug classes to the market. Over the last two decades, target-based screening did not identify new targets and suitable compound classes for development of antibiotic drugs. Apparently, for better prediction of druggable targets, a deeper understanding of cellular functions and the cellular consequences of their inhibition is necessary. Recent advances in bacterial cell biology have demonstrated the astounding degree of functional organization in bacterial cells, where vital processes require elaborate spatiotemporal-control of the components involved. It became obvious that successful antibiotics, subsequent to the well characterized interaction with their primary targets, often trigger pleiotropic downstream effects that cause disintegration of large biosynthetic machineries and eventually network collapse and efficient killing.

We studied various classes of natural compound antibiotics such as lantibiotics and defensins from mammals and invertebrates, glyco- and lipopetides as well as entirely novel classes such as the teixobactin class. Many of these compounds target bacterial cell wall biosynthesis, which is an “old” target pathway, but obviously the very effective for antibiotic attack. Most of these inhibitors form complexes with the bactoprenol-bound intermediates of cell wall biosynthesis, in particular Lipid II, and simultaneously impair the functional organization of the interdependent cell envelope biosynthesis and cell division machineries (1). Many antimicrobial peptides cause massive perturbation of these machineries even without interaction with a defined molecular target. The example of daptomycin (2) will be used to illustrate the complexity of cellular antibiotic activities and to underline the necessity to think beyond mere drug-target interactions for future antibiotic development; “old” target pathways may have more to offer in this direction.

1) Grein F, Schneider T, & H.G. Sahl, Journal of Molecular Biology 431 (18), 3520-3530 (2019) 2) Grein, F, et al., Nature Communications,11 (1), 1-11 (2020)

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