Sortase enzymes are attractive targets for the development of new anti-infective agents against Gram-positive pathogens because they covalently anchor virulence factors to the cell wall. Here we review what is known about the mechanism of sortase mediated protein anchoring and discuss recently identified inhibitors of this new important enzyme family.

Antibacterial properties of 3′,4′-difluoroquercetin (di-F-Q), a fluorine-substituted stable quercetin derivative, were investigated. Even though di-F-Q itself did not show interesting antibacterial activity, treatment of the Staphylococcus aureus strains with di-F-Q resulted in a dose-dependent reduction in biofilm formation with IC 50 values of 1.8 ~ 5.3 mg/L. Also, the antibacterial activity of ceftazidime (CAZ) against carbapenem-resistant Pseudomonas aeruginosa (CRPA) showed eightfold decrease upon combination with di-F-Q. Assessment of the antimicrobial activity of CAZ in combination with di-F-Q against 50 clinical isolates of P. aeruginosa confirmed 15.7% increase in the percentages of susceptible P. aeruginosa isolates upon addition of di-F-Q to CAZ. Further mechanistic studies revealed that di-F-Q affected the antibiotics efflux system in CRPA but not the β-lactamase activity. Thus, di-F-Q was almost equally effective as carbonyl cyanide m-chlorophenyl hydrazine in inhibiting antibiotic efflux by P. aeruginosa. In vivo evaluation of the therapeutic efficacy of CAZ-(di-F-Q) combination against P. aeruginosa showed 20% of the mice treated with CAZ-(di-F-Q) survived after 7 days in IMP carbapenemase-producing multidrug-resistant P. aeruginosa infection group while no mice treated with CAZ alone survived after 2 days. Taken together, di-F-Q demonstrated unique strain-specific antimicrobial properties including anti-biofilm and antibiotic-potentiating activity against S. aureus and P. aeruginosa, respectively. Quercetin (Fig. 1) is one of the most famous flavonoids, and it is characterized by broad spectrum biological activity including antioxidant, anti-inflammatory, antiviral, and anticancer effects 1. Quercetin has also been reported to have a potential as an antibacterial agent 1 , and its anti-biofilm activity against clinical isolates of gram-positive bacteria, albeit low 2 , is noteworthy. However, several unfavorable physicochemical properties of quercetin such as low chemical stability limits its pharmaceutical use. Previously, in order to tackle this problem, we prepared 3′,4′-difluoroquercetin (di-F-Q, Fig. 1) through bioisosteric replacement of the catecholic hydroxyl groups of quercetin with fluorine atoms, which showed significantly improved chemical stability as well as anticancer activity compared with quercetin 3. In this context, antibacterial properties of di-F-Q appears worth investigating and, in this study, we attempted to evaluate antibacterial, anti-biofilm, and antibiotic-potentiating activity of di-F-Q. Materials and methods Materials. Dimethyl sulfoxide (DMSO), crystal violet and phosphate buffered saline (PBS) were purchased from Merck (St. Louis, MO, USA). Mueller-Hinton broth (MHB) and tryptic soy broth (TSB) were obtained from BD Biosciences (San Jose, CA, USA) and Fisher Scientific (Pittsburgh, PA, USA), respectively.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by memory and cognitive impairments. Neurogenesis, which is related to memory and cognitive function, is reduced in the brains of patients with AD. Therefore, enhancing neurogenesis is a potential therapeutic strategy for neurodegenerative diseases, including AD. Hesperidin (HSP), a bioflavonoid found primarily in citrus plants, has anti-inflammatory, antioxidant, and neuroprotective effects. The objective of this study was to determine the effects of HSP on neurogenesis in neural stem cells (NSCs) isolated from the brain of mouse embryos and five familial AD (5xFAD) mice. In NSCs, HSP significantly increased the proliferation of NSCs by activating adenosine monophosphate (AMP)-activated protein kinase (AMPK)/cAMP-response element-binding protein (CREB) signaling, but did not affect NSC differentiation into neurons and astrocytes. HSP administration restored neurogenesis in the hippocampus of 5xFAD mice via AMPK/brain-derived neurotrophic factor/tropomyosin receptor kinase B/CREB signaling, thereby decreasing amyloid-beta accumulation and ameliorating memory dysfunction. Collectively, these preclinical findings suggest that HSP is a promising candidate for the prevention and treatment of AD.

Upon single treatment against Staphylococus aureus, quercetin-pivaloxymethyl conjugate (Q-POM) had antibacterial activities with minimum inhibitory concentrations (MICs) of 16-32 mg/L. Q-POM showed MIC of 32 mg/L against vancomycin-resistant Enterococcus faceium (VRE), which is remarkably lower than other antibiotics investigated (≥256 mg/L). Under sub-MIC concentrations, Q-POM potentiated the activity of ampicillin, cefepime, and vancomycin against S. aureus and Enterococcus (including highly resistant strains such as hetero-resistant vancomycin-intermediate S. aureus (hVISA), vancomycin-intermediate S. aureus (VISA), and VRE), by decreasing the MICs of these antibiotics by 4-128 folds. Q-POM was found to be partially synergistic with ampicillin and cefepime against S. aureus and Enterococcus, while it was strongly synergistic with vancomycin. Q-POM at 5 mg/L inhibited the formation of biofilms of S. aureus by 24-83% and VRE by 70%. Additionally, Q-POM inhibited the hemolytic activity of S. aureus in a dose-dependent manner. Cytotoxic activity was evaluated in human liver epithelial cells (HepG2), and the 50% cytotoxicity concentration (CC 50) value of Q-POM was higher than 50 mg/L. These results indicate the potential use of Q-POM in treatment of methicillin-resistant Staphylococcus aureus (MRSA) and VRE infections.

Identifying infection transmission routes in hospitals may prevent the spread of respiratory viruses and mass infections. Most previous related research focused on the air movement of passive tracers, which typically represent breathing. In this study, particle evaporation and dispersions with various particle sizes were applied to evaluate particle movement because of breathing and coughing using computational fluid dynamics (CFD) simulations. Pyeongtaek St. Mary Hospital, where a Middle East respiratory syndrome (MERS) index patient infected several patients on the same floor, was used for a case study. We compared the dispersion characteristics of various particle sizes and validated results by comparing infection rates in different ward. Results indicated that droplets spread across the corridor and dispersed to wards that were more than 17 m apart from the index patient by natural ventilation. Droplets from exhaled breath under steady-state simulation showed a wider range of dispersion than cough droplets under transient simulation, but cough droplet dispersion was more consistent with the actual infection rate in each ward. Cough droplets sized under 75 µm evaporated to 26% of the initial size and started to disperse into the corridor within one minute; in nine minutes, droplets dispersed throughout every ward. This study may increase awareness on the dispersion characteristics of infectious particles.