We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains ofStaphylococcus aureus,Escherichia coli, andPseudomonas aeruginosa. We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory–calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.
more »
« less
Photocatalytic and Photothermal Antimicrobial Mussel-Inspired Nanocomposites for Biomedical Applications
Bacterial infection has traditionally been treated with antibiotics, but their overuse is leading to the development of antibiotic resistance. This may be mitigated by alternative approaches to prevent or treat bacterial infections without utilization of antibiotics. Among the alternatives is the use of photo-responsive antimicrobial nanoparticles and/or nanocomposites, which present unique properties activated by light. In this study, we explored the combined use of titanium oxide and polydopamine to create nanoparticles with photocatalytic and photothermal antibacterial properties triggered by visible or near-infrared light. Furthermore, as a proof-of-concept, these photo-responsive nanoparticles were combined with mussel-inspired catechol-modified hyaluronic acid hydrogels to form novel light-driven antibacterial nanocomposites. The materials were challenged with models of Gram-negative and Gram-positive bacteria. For visible light, the average percentage killed (PK) was 94.6 for E. coli and 92.3 for S. aureus. For near-infrared light, PK for E. coli reported 52.8 and 99.2 for S. aureus. These results confirm the exciting potential of these nanocomposites to prevent the development of antibiotic resistance and also to open the door for further studies to optimize their composition in order to increase their bactericidal efficacy for biomedical applications.
more »
« less
- Award ID(s):
- 1936519
- PAR ID:
- 10497828
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- International Journal of Molecular Sciences
- Volume:
- 24
- Issue:
- 17
- ISSN:
- 1422-0067
- Page Range / eLocation ID:
- 13272
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Each year, thousands of patients die from antimicrobial‐resistant bacterial infections that fail to respond to conventional antibiotic treatment. Antimicrobial polymers are a promising new method of combating antibiotic‐resistant bacterial infections. We have previously reported the synthesis of a series of narrow‐spectrum peptidomimetic antimicrobial polyurethanes that are effective against Gram‐negative bacteria, such asEscherichia coli; however, these polymers are not effective against Gram‐positive bacteria, such asStaphylococcus aureus. With the aim of understanding the correlation between chemical structure and antibacterial activity, we have subsequently developed three structural variants of these antimicrobial polyurethanes using post‐polymerization modification with decanoic acid and oleic acid. Our results show that such modifications converted the narrow‐spectrum antibacterial activity of these polymers into broad‐spectrum activity against Gram‐positive species such asS. aureus, however, also increasing their toxicity to mammalian cells. Mechanistic studies of bacterial membrane disruption illustrate the differences in antibacterial action between the various polymers. The results demonstrate the challenge of balancing antimicrobial activity and mammalian cell compatibility in the design of antimicrobial polymer compositions. © 2019 Society of Chemical Industrymore » « less
-
Synthesis of new, highly active antibacterial agents has become increasingly important in light of emerging antibiotic resistance. In the present study, ZnO/graphene quantum dot (GQD) nanocomposites were produced by a facile hydrothermal method and characterized by an array of microscopic and spectroscopic measurements, including transmission electron microscopy, X-ray photoelectron spectroscopy, UV-vis and photoluminescence spectroscopy. Antibacterial activity of the ZnO/GQD nanocomposites was evaluated with Escherichia coli within the context of minimum inhibitory concentration and the reduction of the number of bacterial colonies in a standard plate count method, in comparison to those with ZnO and GQD separately. It was found that the activity was markedly enhanced under UV photoirradiation as compared to that in ambient light. This was ascribed to the enhanced generation of reactive oxygen species under UV photoirradiation, with minor contributions from membrane damage, as manifested in electron paramagnetic resonance and fluorescence microscopic measurements. The results highlight the significance of functional nanocomposites based on semiconductor nanoparticles and graphene derivatives in the development of effective bactericidal agents.more » « less
-
The Atacama Desert, the driest, with the highest radiation, and one of the most ancient deserts in the world, is a hostile environment for life. We have a collection of 74 unique bacterial isolates after cultivation and confirmation by 16S rRNA gene sequencing. Pigmentation, biofilm formation, antimicrobial production againstEscherichia coliMG1655 andStaphylococcus aureusHG003, and antibiotic resistance were assessed on these isolates. We found that approximately a third of the colonies produced pigments, 80% of isolates formed biofilms, many isolates produce growth inhibiting activities againstE. coliand/orS. aureus, and many were resistant to antibiotics. The functional characterization of these isolates gives us insight into the adaptive bacterial strategies in harsh environments and enables us to learn about their possible use in agriculture, healthcare, or biotechnology.more » « less
-
null (Ed.)Abstract This paper presents research results of biocidal effect of thermoplastic- polyester-elastomer (TPE-E) with incorporation of hybrid Ag/ZnO/SiO 2 NPs (silver/Zinc oxide/SiO 2 nanoparticles). These results were compared with various gamma-irradiated doses and processing techniques including extrusion, injection molding and compression molding. In all these processing techniques the TPE-E was mixed with mineral oil and Ag/ZnO/SiO 2 nanoparticles. The TPE-E nanocomposites were characterized by differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), Infrared FT spectroscopy (FTIR), surface enhanced Raman technique ( SERS), FESEM (Field emission scanning electron microscopy), Energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), TEM (transmission electronic microscopy) and antimicrobial test. Antibacterial activity against E. coli and S. aureus , are reported and these results showed potential application in health care products.more » « less
An official website of the United States government

