A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Abstract

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

Figure 1

General structure of the cyclolipopeptide analogs (upper left, analog 1, see Table 1). The structural and chemical features discussed for the design of the analogs are highlighted. Natural polymyxin B is shown below. The structure of lanreotide (right), a commercially available disulfide cyclic peptide having two D-amino acids is shown for comparison. Lanreotide is used for the treatment of acromegaly and neuroendocrine tumours and some 100-200 Kg are produced every year worldwide.

Figure 2. TEM micrographs of treated E. coli.

a,b, after treatment with PxB (0.5 μg/mL) numerous protrusions (solid arrow) from the cell surface are observed. c,d, after treatment with lipopeptide 38 (2 μg/mL) the effect is diverse, showing numerous membranous structures, protrusions of the membrane similar to PxB (dashed arrow).

Figure 3. TEM micrographs of treated S. aureus.

a,b, after treatment with lipopeptide 38 (4 μg/mL), mesosome-like structures and defects on the cell wall can be observed.