Pseudomonas aeruginosa, one of the most intractable Gram-negative bacteria, has become a public health threat due to its outer polysaccharide layer, efflux transporter system, and high level of biofilm formation, all of which contribute to multi-drug resistance. Even though it is a pathogen of the highest concern, the status of the antibiotic development pipeline is unsatisfactory. In this review, we summarize marine natural products (MNPs) isolated from marine plants, animals, and microorganisms which possess unique structures and promising antibiotic activities against P. aeruginosa. In the last decade, nearly 80 such MNPs, ranging from polyketides to alkaloids, peptides, and terpenoids, have been discovered. Representative compounds exhibited impressive in vitro anti-P. aeruginosa activities with MIC values in the single-digit nanomolar range and in vivo efficacy in infectious mouse models. For some of the compounds, the preliminary structure-activity-relationship (SAR) and anti-bacterial mechanisms of selected compounds were introduced. Compounds that can disrupt biofilm formation or membrane integrity displayed potent inhibition of multi-resistant clinical P. aeruginosa isolates and could be considered as lead compounds for future development. Challenges on how to translate hits into useful candidates for clinical development are also proposed and discussed.
SH2 domains have been recognized as promising targets
for various
human diseases. However, targeting SH2 domains with phosphopeptides
or small-molecule inhibitors derived from bioisosteres of the phosphate
group is still challenging. Identifying novel bioisosteres of the
phosphate group to achieve favorable in vivo potency
is urgently needed. Here, we report the feasibility of targeting the
STAT3-SH2 domain with a boronic acid group and the identification
of a highly potent inhibitor compound 7 by replacing
the carboxylic acid of compound 4 with a boronic acid.
Compound 7 shows higher binding affinity, better cellular
potency, more favorable PK profiles, and higher in vivo antitumor activity than 4. The stronger anticancer
effect of 7 partially stems from its covalent binding
mode with the SH2 domain, verified by the washout experiments. The
relatively high level of sequence conservation among SH2 domains makes
the results presented here of general significance.
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