Bifunctional antimicrobial conjugates and hybrid antimicrobials P. Klahn * ab and M. Br ¨ onstrup * a Covering: up to the end of 2016 Novel antimicrobial drugs are continuously needed to counteract bacterial resistance development. An innovative molecular design strategy for novel antibiotic drugs is based on the hybridization of an antibiotic with a second functional entity. Such conjugates can be grouped into two major categories. In the first category (antimicrobial hybrids), both functional elements of the hybrid exert antimicrobial activity. Due to the dual targeting, resistance development can be significantly impaired, the pharmacokinetic properties can be superior compared to combination therapies with the single antibiotics, and the antibacterial potency is often enhanced in a synergistic manner. In the second category (antimicrobial conjugates), one functional moiety controls the accumulation of the other part of the conjugate, e.g. by mediating an active transport into the bacterial cell or blocking the efflux. This approach is mostly applied to translocate compounds across the cell envelope of Gram-negative bacteria through membrane-embedded transporters (e.g. siderophore transporters) that provide nutrition and signalling compounds to the cell. Such ‘Trojan Horse’ approaches can expand the antibacterial activity of compounds against Gram-negative pathogens, or offer new options for natural products that could not be developed as standalone antibiotics, e.g. due to their toxicity. 1 Introduction 2 Strategies to overcome resistance in antimicrobial drug development 3 Hybrid antimicrobials 3.1 Fluoroquinolone- and quinolone-containing hybrids 3.2 Aminoglycoside-containing hybrids 3.3 Glycopeptide-containing hybrids 3.4 Miscellaneous hybrid antimicrobials containing small molecule antibiotics 3.5 Hybrids of antimicrobials with drugs against other coinfections 4 Bifunctional antimicrobial conjugates containing AMPs, CPPs and lipopeptides 5 Bacterial cell envelopes and embedded translocation systems 6 Siderophore–antibiotic conjugates for the targeted trans- location towards bacterial membrane barriers 6.1 Siderophore–drug conjugates derived from pyoverdine and pyochelin 6.2 Catecholate siderophore–drug conjugates derived from aminochelin, azotochelin, protochelin, agrobactin, enterobactin, and salmochelins 6.3 Hydroxamate siderophore–drug conjugates derived from ferrioxamine B, danoxamine and ferrichrome 6.4 Siderophore–drug conjugates derived from designed and naturally occurring mixed-type siderophores 6.5 Merged siderophore–drug hybrids 7 Miscellaneous conjugates enhancing drug accumulation 8 Conclusions 9 Acknowledgements 10 Notes and references 1 Introduction Bacterial resistance to antimicrobial drugs might become one of the biggest threats to human health in our times. The increasing occurrence of infections with multi-drug-resistant pathogens is associated with high mortality and morbidity, 1–3 and the prevailing lack of new efficient antimicrobial drugs for treatment of these infections has led to serious concerns of an imminent fall-back into a so-called pre-antibiotic era. 4–6 Bacte- rial resistance to antimicrobial drugs has to be understood as an intrinsic part of bacterial evolution, 7,8 and its genetic basis can arise via two main ways: 9 either direct via chromosomal a Department for Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany. E-mail: Mark.Broenstrup@ helmholtz-hzi.de b Institute for Organic Chemistry, Technische Universit¨ at Braunschweig, Hagenring 30, 38106 Braunschweig, Germany. E-mail: P.Klahn@tu-braunschweig.de Cite this: DOI: 10.1039/c7np00006e Received 24th January 2017 DOI: 10.1039/c7np00006e rsc.li/npr This journal is © The Royal Society of Chemistry 2017 Nat. Prod. Rep. Natural Product Reports REVIEW Published on 22 May 2017. Downloaded by Technische Universitat Braunschweig on 22/05/2017 12:58:34. View Article Online View Journal