To cope with the global bacterial multidrug resistance, scientific communities have devoted significant efforts to develop novel antibiotics, particularly those with new modes of actions. Teixobactin, recently isolated from uncultured bacteria, is considered as a promising first-in-class drug candidate for clinical development. Herein, we report its total synthesis by a highly convergent Ser ligation approach and this strategy allows us to prepare several analogues of the natural product.
A convergent
synthesis via the late-stage serine ligation of naturally
occurring calcium-dependent antibiotic CDA3a and its analogues has
been developed, which allowed us to readily synthesize the analogues
with the variation on the lipid tail. Some analogues were found to
show 100–500-fold higher antimicrobial activity than the natural
compound CDA3a against drug resistant bacteria. This study will enhance
our understanding of CDA3a and provide valuable antibacterial lead
candidates for further development.
Convergent Ser/Thr ligation has been used to prepare a series of teixobactin analogues (28 in total) to establish a structure-activity relationship of teixobactin. anti-bacterial evaluations of these synthetic analogues have revealed the critical amino acid residues and the sites tolerable of modifications. These studies will shed lights on the further development of teixobactin analogues with improved antibacterial activities.
Daptomycin is effective
in treating infections caused by antibiotic-resistant
Gram-positive pathogens, including methicillin-resistant Staphylococcus
aureus (MRSA), vancomycin-resistant Enterococci (VRE), and vancomycin-resistant S. aureus (VRSA).
Due to its distinct mechanism of action toward multidrug-resistant
bacteria, daptomycin provides an attractive structural motif to generate
new daptomycin-based antibiotics to combat the problem of bacterial
resistance. In this study, we used the total synthesis method to produce
daptomycin analogues with a variety in terms of types and sites of
modifications. Five classes of daptomycin analogues were synthesized,
and the antimicrobial activities of the analogues were analyzed by
several biological assays. From this study, we established a comprehensive
structure–activity relationship of daptomycin which will lay
the foundation for the further development of daptomycin-based antibiotics.
The development of novel antibiotics is critical to combating the growing emergence of drug-resistant pathogens. Malacidin A is a new member of the calcium-dependent antibiotic (CDAs) family with activity against antibioticresistant pathogens. Its mode of action is distinct from classical CDAs. However, the absolute structure of malacidin A has not been established. Herein, the total syntheses of malacidin A and its analogues are reported by a combination of Fmocbased solid-phase peptide synthesis (SPPS) and b-hydroxyaspartic acid ligation-mediated peptide cyclization. The total synthesis enabled us to establish the absolute configuration of malacidin A, which is in agreement with those for natural malacidin A confirmed by advanced Marfeys analysis in our study.
Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the nonproteinogenic amino acid kynurenine in daptomycin could result in significant enhancement of antibacterial activity. Termed "kynomycin," this new antibiotic exhibits higher antibacterial activity than daptomycin and is able to eradicate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains, including daptomycin-resistant strains. The improved antimicrobial activity of kynomycin was demonstrated in in vitro time-killing assay, in vivo wax worm model, and different mouse infection models. The increased antibacterial activity, improved pharmacokinetics, and lower cytotoxicity of kynomycin, compared to daptomycin, showed the promise of the future design and development of next-generation daptomycin-based antibiotics.
An
aqueous dispersion of polyethylenimine-modified graphene oxide
(PEI-GO) was prepared via a one-step synthesis through an epoxy ring-opening
reaction. PEI-GO exhibited bacterial growth inhibition activity on
methicillin-resistant Staphylococcus aureus (MRSA)
with a minimum inhibitory concentration as low as 8 μg mL–1. Time–kill curve assay and SYTOX Green assay
showed the antibacterial activity and bacteria cell membrane permeability
of PEI-GO, respectively. Most importantly, when PEI-GO was employed
at 1–2 μg mL–1, a synergistic effect
with daptomycin to resensitize daptomycin-resistant MRSA was revealed.
A synergistic effect between PEI-GO and daptomycin provides a possible
way to increase bacterial killing and reduce the development of daptomycin
resistance. The antibacterial activity of PEI-GO is attributed to
the damaged cell membrane caused by the sharp edge and chain structure
of the PEI-GO nanosheets as well as the high density of amine groups
present in the PEI chains. Our results indicate that PEI-GO dispersion
has a great potential for clinical pathogenic bacteria treatment.
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