The outbreak of coronavirus disease 2019 (COVID-19) has resulted in
a global pandemic due to the rapid spread of severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of
this manuscript’s publication, remdesivir is the only
COVID-19 treatment approved by the United States Food and Drug
Administration. However, its effectiveness is still under
question due to the results of the large Solidarity Trial
conducted by the World Health Organization. Herein, we report
that the parent nucleoside of remdesivir, GS-441524, potently
inhibits the replication of SARS-CoV-2 in Vero E6 and other cell
lines. Challenge studies in both an AAV-hACE2 mouse model of
SARS-CoV-2 and in mice infected with murine hepatitis virus, a
closely related coronavirus, showed that GS-441524 was highly
efficacious in reducing the viral titers in CoV-infected organs
without notable toxicity. Our results support that GS-441524 is
a promising and inexpensive drug candidate for treating of
COVID-19 and other CoV diseases.
Sulfur fluoride exchange (SuFEx), a next generation of click chemistry, opens an avenue for drug discovery. We report here the discovery and structure–activity relationship studies of a series of arylfluorosulfates, synthesized via SuFEx, as antibacterial agents. Arylfluorosulfates 3, 81, and 101 showed potency to overcome multidrug resistance and were not susceptible to the generation of resistance. They exhibited rapid bactericidal potency and selectively killed gram-positive bacterial strains. These compounds also exhibited the ability to disrupt established bacterial biofilm and kill persisters derived from biofilm. Furthermore, arylfluorosulfate 3 had a synergistic effect with streptomycin and gentamicin. In addition, their anti-MRSA potency was evaluated and determined by the Caenorhabditis elegans model.
Noninvasive
photothermal therapy (PTT) is an emerging strategy
for eliminating multidrug-resistant (MDR) bacteria that achieve sterilization
by generating temperatures above 50 °C; however, such a high
temperature also causes collateral damage to healthy tissues. In this
study, we developed a low-temperature PTT based on borneol-containing
polymer-modified MXene nanosheets (BPM) with bacteria-targeting capabilities.
BPM was fabricated through the electrostatic coassembly of negatively
charged two-dimensional MXene nanosheets (2DM) and positively charged
quaternized α-(+)-borneol-poly(N,N-dimethyl ethyl methacrylate) (BPQ) polymers. Integrating BPQ with
2DM improved the stability of 2DM in physiological environments and
enabled the bacterial membrane to be targeted due to the presence
of a borneol group and the partially positive charge of BPQ. With
the aid of near-infrared irradiation, BPM was able to effectively
eliminate methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli) through targeted photothermal hyperthermia.
More importantly, BPM effectively eradicated more than 99.999% (>5
orders of magnitude) of MRSA by localized heating at a temperature
that is safe for the human body (≤40 °C). Together, these
findings suggest that BPM has good biocompatibility and that membrane-targeting
low-temperature PTT could have great therapeutic potential against
MDR infections.
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