Modified host defence peptides as beta-lactamase-dependent antibiotic prodrug candidates.
Infections caused by antibiotic resistant bacteria have been listed as top priority diseases by the World Health Organisation (WHO) in terms of their threat to global public health if the need for novel medicines is not met. Host defence peptides (HDPs) are multifunctional molecular effectors of innate immunity, the first line of defence against infection in multicellular organisms. They are characterised by an antimicrobial activity essentially directed at a universal non-protein target (bacterial membrane(s)), complemented by multiple immunomodulatory and anti-inflammatory activities. They are recognised as promising candidates for the development of novel antimicrobial and anti-inflammatory agents, owing to their original and selective mode of action which may circumvent the limitations of classical antibiotics in terms of drug resistance. Despite their potential in medicine, these 'Nature's antibiotics' have not yet been approved for use as drugs. Their main limitations are a risk of unpredictable side-effects when administered systemically and a lack of stability limiting their efficacy. Several approaches have been proposed to achieve clinical success with host defence peptides, such as conversion into peptidomimetics, liposomal delivery and a prodrug strategy. Prodrugs are pharmacologically inactive molecules metabolised to an active agent. Ideally this metabolic step is catalysed by an enzyme confined to a targeted body site andlor associated with a pathological process. Despite the potential of this approach, no inactive precursors of host defence peptides eligible for disease site specific activation have been reported to date. The present project aimed at developing prodrugs of host defence peptides by conjugating selected candidates to a p-lactam molecule (cephalosporin) as a promoiety. These components are joined by a linker which can release the peptide upon degradation of the cephalosporin by a p-lactamase (elimination promoted-immolative carbamate linker). The technology required to unequivocally and efficiently conjugate a peptide to a cephalosporin has been developed and applied to the successful preparation of P-lactamase-dependent prodrug candidates of host defence peptides, the fmt to be reported for these mediators of innate immunity.