Recent advances in the exploration of oxazolidinone scaffolds from compound development to antibacterial agents and other bioactivities.

Bacterial infections cause a variety of life-threatening diseases, and the continuous evolution of drug-resistant bacteria poses an increasing threat to current antimicrobial regimens. Gram-positive bacteria (GPB) have a wide range of genetic capabilities that allow them to adapt to and develop resistance to practically all existing antibiotics. Oxazolidinones, a class of potent bacterial protein synthesis inhibitors with a unique mechanism of action involving inhibition of bacterial ribosomal translation, has emerged as the antibiotics of choice for the treatment of drug-resistant GPB infections. In this review, we discussed the oxazolidinone antibiotics that are currently on the market and in clinical development, as well as an updated synopsis of current advances on their analogues, with an emphasis on innovative strategies for structural optimization of linezolid, structure-activity relationship (SAR), and safety properties. We also discussed recent efforts aimed at extending the activity of oxazolidinones to gram-negative bacteria (GNB), antitumor, and coagulation factor Xa. Oxazolidinone antibiotics can accumulate in GNB by a conjugation to siderophore-mediated ß-lactamase-triggered release, making them effective against GNB.

Design, synthesis and antibacterial evaluation of low toxicity amphiphilic-cephalosporin derivatives.

Global public health is facing a serious problem as a result of the rise in antibiotic resistance and the decline in the discovery of new antibiotics. In this study, two series of amphiphilic-cephalosporins were designed and synthesized, several of which showed good antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships indicated that the length of the hydrophobic alkyl chain significantly affects the antibacterial activity against Gram-negative bacteria. The best compound 2d showed high activity against drug-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) with MICs of 0.5 and 2-4 µg/mL, respectively. Furthermore, 2d remained active in complex mammalian body fluids and had a longer post-antibiotic effect (PAE) than vancomycin. Mechanism studies indicated that compound 2d lacks membrane-damaging properties and can target penicillin-binding proteins to disrupt bacterial cell wall structure, inhibit the metabolic activity and induce the accumulation of reactive oxygen species (ROS) in bacteria. Compound 2d showed minimal drug resistance and was nontoxic to HUVEC and HBZY-1 cells with CC50 > 128 µg/mL. These findings suggest that 2d is a promising drug candidate for treating bacterial infections.

Effective ciprofloxacin cationic antibacterial agent against persister bacteria with low hemolytic toxicity.

With the widespread use of antibiotics, bacterial resistance has developed rapidly. To make matters worse, infections caused by persistent bacteria and biofilms often cannot be completely eliminated, which brings great difficulties to clinical medication. In this work, three series of quinolone pyridinium quaternary ammonium small molecules were designed and synthesized. Most of the compounds showed good antibacterial activity against Gram-positive bacteria (S. aureus and E. faecalis) and Gram-negative bacteria (E. coli and S. maltophilia). The activity of the para-pyridine quaternary ammonium salt was better than that of the meta-pyridine. 3f was the optimal compound with good stability in body fluids and was unlikely to induce bacterial resistance. The hemolysis rate of erythrocytes at 1280 µg/mL for 3f was only 5.1%. Encouragingly, 3f rapidly killed bacteria within 4 h at 4 × MIC concentration and was effective in killing persistent bacteria in biofilms. The antibacterial mechanism experiments showed that 3f could cause disorder of bacterial membrane potential, increase bacterial membrane permeability, dissolve and destroy the membrane. Incomplete bacterial membranes lead to leakage of bacterial genetic material, concomitant production of ROS, and bacterial death due to these multiple effects.

CPP-Net: Context-aware Polygon Proposal Network for Nucleus Segmentation.

Nucleus segmentation is a challenging task due to the crowded distribution and blurry boundaries of nuclei. To differentiate between touching and overlapping nuclei, recent approaches have represented nuclei in the form of polygons, and have accordingly achieved promising performance. Each polygon is represented by a set of centroid-to-boundary distances, which are in turn predicted by features of the centroid pixel for a single nucleus. However, the use of the centroid pixel alone does not provide sufficient contextual information for robust prediction and therefore affects the segmentation accuracy. To address this problem, we propose a Context-aware Polygon Proposal Network (CPP-Net) for nucleus segmentation. First, we sample a point set rather than a single pixel within each cell for distance prediction; this strategy substantially enhances the contextual information and thereby improves the prediction robustness. Second, we propose a Confidence-basedWeighting Module, which adaptively fuses the predictions from the sampled point set. Third, we introduce a novel Shape-Aware Perceptual (SAP) loss that constrains the shape of the predicted polygons. This SAP loss is based on an additional network that is pre-trained by means of mapping the centroid probability map and the pixel-to-boundary distance maps to a different nucleus representation. Extensive experiments demonstrate the effectiveness of each component in the proposed CPP-Net. Finally, CPP-Net is found to achieve state-of-the-art performance on three publicly available databases, namely DSB2018, BBBC06, and PanNuke. The code of this paper will be released.

Development of biaromatic core-linked antimicrobial peptide mimics: Substituent position significantly affects antibacterial activity and hemolytic toxicity.

The development of bacterial resistance to the majority of clinically significant antimicrobials has made it more difficult to treat bacterial infections with conventional antibiotics. As part of ongoing research on antimicrobial peptide mimetics, a series of quaternary ammonium cationic compounds with various linkers were designed and synthesized, with some demonstrating high antibacterial activity against Gram-negative and Gram-positive bacteria. The structure-activity relationship study revealed that the spatial position of substituents had a significant impact on antibacterial activity and hemolytic toxicity. The best compound, 3e, has good antibacterial activity against Staphylococcus aureus [minimum inhibitory concentration (MIC = 1 µg/mL)] and the least hemolytic toxicity [hemolytic concentration (HC50 = 905 µg/mL)], is stable in mammalian body fluids, and rarely induces bacterial resistance. The mechanism study revealed that the membrane action mode may be its potential bactericidal mechanism, and it can effectively cause the accumulation of intracellular reactive oxygen species (ROS) for killing bacteria. Importantly, 3e can effectively reduce the load of methicillin-resistant Staphylococcus aureus (MRSA) in mouse skin and has a higher in vivo bactericidal efficiency than vancomycin. These findings highlight the significance of divergent linkers in quaternary ammonium cations as antimicrobial peptide mimics and the potential of these cations to treat bacterial infections.

Antibacterial efficacy evaluation and mechanism probe of small lysine chalcone peptide mimics.

Bacterial resistance is a growing threat to public health and a significant barrier to anti-infective treatment. Consequently, the development of novel antibacterial strategies to address this issue is critical. Herein, we developed a series of chalcone-alkyl-lysine compounds by mimicking the chemical structure and antibacterial properties of cationic antimicrobial peptides. Most of the compounds showed significant antibacterial activity against Gram-positive and Gram-negative bacteria. Compound 6d displayed potent antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), with MICs of 1-4 µg/mL. In addition, 6d exhibited excellent antibacterial activity against clinical MRSA and NDM-positive isolates, bactericidal properties, low resistance frequency. The mechanism studies revealed that compound 6d destroys bacterial cell membranes by interacting with phosphatidylglycerol (PG), causing the production of reactive oxygen species (ROS) and the leakage of nucleic acids, resulting in bacterial death. Furthermore, compound 6d did not exhibit any observable toxicity in HeLa and HEK293 cells at 8 × MIC. As a result, the findings suggest that compound 6d has potential therapeutic effects against bacterial infections and could be a promising drug candidate for future research.