Synthetic polymeric antimicrobials have received enormous attention recently on the back of increasing multidrug-resistance microbes. While conventional small molecular antibiotics act on specific targets to inhibit microbe activities, macromolecular antimicrobials physically destroy cell membranes of the organism rendering them ineffective; the mechanism of the latter aids in the prevention of developing drug-resistance microbes. In this investigation, we report on the synthesis of biodegradable cationic polycarbonates containing propyl and hexyl side chains quaternized with various nitrogen-containing heterocycles, such as imidazoles and pyridines, and their in vitro antimicrobial application. These polymers demonstrate a wide spectrum of activity (using minimum inhibitory concentrations analysis) against Staphylococcus aureus (Gram-positive), Escherichia coli (Gram-negative), Pseudomonas aeruginosa (Gram-negative), and Candida albicans (fungus). Hemolysis experiments also show high selectivity toward the tested microbes over mammalian (rat) red blood cells (rRBCs). In particular, some of the polymers can achieve >250 times selectivity of S. aureus over rRBCs. In addition, the polymers function via a membrane-lytic mechanism; hence, they are less likely to develop drug resistance. All these properties make them ideal candidates as antimicrobial agents.
In this study, bortezomib (BTZ, a cytotoxic water-insoluble anticancer drug) was encapsulated in micellar nanoparticles having a catechol-functionalized polycarbonate core through a pH-sensitive covalent bond between phenylboronic acid (PBA) in BTZ and catechol, and these drug-loaded micelles were incorporated into hydrogels to form micelle/hydrogel composites. A series of injectable, biodegradable hydrogels with readily tunable mechanical properties were formed and optimized for sustained delivery of the BTZ-loaded micelles through ionic coacervation between PBA-functionalized polycarbonate/poly(ethylene glycol) (PEG) "ABA" triblock copolymer and a cationic one having guanidinium- or thiouronium-functionalized polycarbonate as "A" block. An in vitro release study showed the pH dependence in BTZ release. At pH 7.4, the BTZ release from the micelle/hydrogel composite remained low at 7%, whereas in an acidic environment, ∼85% of BTZ was released gradually over 9 days. In vivo studies performed in a multiple myeloma MM.1S xenograft mouse model showed that the tumor progression of mice treated with BTZ-loaded micelle solution was similar to that of the control group, whereas those treated with the BTZ-loaded micelle/hydrogel composite resulted in significant delay in the tumor progression. The results demonstrate that this hydrogel has great potential for use in subcutaneous and sustained delivery of drug-loaded micelles with superior therapeutic efficacy.
The high prevalence of catheter-associated infections accounts for more than 3 billion dollars annually in hospitals, and antimicrobial polymer coatings on catheter surface may serve as an attractive weapon to mitigate infections. Triblock polycarbonate polymers consisting of three critical components including antifouling poly(ethylene glycol) (PEG), antimicrobial cationic polycarbonate, and a tethering or adhesive functional block were synthesized. In this study, the block topology or placement of the distinctive blocks was varied and their efficacy as antimicrobial and antifouling agents investigated on coated surfaces. The individual blocks were designed to have comparable lengths that were subsequently grafted onto a prefunctionalized catheter surface through covalent bonding under mild conditions. The anchoring/adhesive functional moiety based on a maleimide functional carbonate was positioned at either the center or end of the polymer block and subsequently tethered to the surface via Michael addition chemistry. The placement of the adhesive block was investigated in terms of its effect on antimicrobial and antifouling properties. The surface coated with the polymer containing the center-positioned tethering block (2.4k-V) was unable to prevent bacteria fouling, even though demonstrated higher bacteria killing efficacy in solution as compared to the surface coated with the polymer containing the end-positioned tethering block (2.4k-S). In contrast, the 2.4k-S coating resisted fouling of both Gram-positive S. aureus and Gram-negative E. coli effectively under conditions that simulate the device lifetime (1 week). Moreover, the coating prevented protein fouling and platelet adhesion without inducing significant hemolysis. Consequently, this antibacterial and antifouling polymer coating is an interesting candidate to prevent catheter-associated bloodstream infections.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002–2003. Horseshoe bats (genus Rhinolophus) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related to SARS-CoV-2, has been identified in one horseshoe-bat species. Here we characterize the ability of the S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, pangolin coronavirus (PgCoV), RaTG13, and LyRa11, a bat virus similar to SARS-CoV-1, to bind a range of ACE2 orthologs. We observed that the PgCoV RBD bound human ACE2 at least as efficiently as the SARS-CoV-2 RBD, and that both RBDs bound pangolin ACE2 efficiently. We also observed a high level of variability in binding to closely related horseshoe-bat ACE2 orthologs consistent with the heterogeneity of their RBD-binding regions. However five consensus horseshoe-bat ACE2 residues enhanced ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 pseudoviruses by an enzymatically inactive immunoadhesin form of human ACE2 (hACE2-NN-Fc). Two of these mutations impaired neutralization of SARS-CoV-1 pseudoviruses. An hACE2-NN-Fc variant bearing all five mutations neutralized both SARS-CoV-2 pseudovirus and infectious virus more efficiently than wild-type hACE2-NN-Fc. These data suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of soluble ACE2.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.