New infection treatments are urgently needed to combat the rising threat of multi-drug resistant
bacteria. Despite early clinical set-backs attention has re-focused on host defense proteins
(HDPs), as potential sources for new and effective antimicrobial treatments. HDPs appear to act at
multiple targets and their repertoire includes disruptive membrane and intracellular activities against
numerous types of pathogens as well as immune modulatory functions in the host. Importantly, these
novel activities are associated with a low potential for emergence of resistance and little crossresistance
with other antimicrobial agents. Based on these properties, HDPs appear to be ideal candidates
for new antibiotics; however, their development has been plagued by the many therapeutic limitations
associated with natural peptidic agents. This review focuses on HDP mimetic approaches
aimed to improve metabolic stability, pharmacokinetics, safety and manufacturing processes. Early efforts
with β-peptide or peptoid analogs focused on recreating stable facially amphiphilic structures but
demonstrated that antimicrobial activity was modulated by more, complex structural properties. Several
approaches have used lipidation to increase the hydrophobicity and membrane activity. One lead
compound, LTX-109, has entered clinical study as a topical agent to treat impetigo and nasal decolonization.
In a more significant departure from the amino acid like peptidomimetics, considerable effort
has been directed at developing amphiphilic compounds that recapitulate the structural and biological
properties of HDPs on small abiotic scaffolds. The lead compound from this approach, brilacidin, has
completed two phase 2 studies as an intravenous agent for skin infections.
Keywords: Antibiotic, Antimicrobial peptides, Antiseptic, Host defense proteins, In vivo, LPS, LTA, Membrane, Mimetics,
Mimics, Pharmacokinetics, Resistance, Therapeutic, TNF.
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