Vancomycin-resistant enterococci (VRE) are the second leading cause of hospital-acquired infections (HAIs) attributed to a drug-resistant bacterium in the United States, and resistance to the frontline treatments is well documented. To combat VRE, we have repurposed the FDA-approved carbonic anhydrase drug acetazolamide to design potent antienterococcal agents. Through structure–activity relationship optimization we have arrived at two leads possessing improved potency against clinical VRE strains from MIC = 2 μg/mL (acetazolamide) to MIC = 0.007 μg/mL (22) and 1 μg/mL (26). Physicochemical properties were modified to design leads that have either high oral bioavailability to treat systemic infections or low intestinal permeability to treat VRE infections in the gastrointestinal tract. Our data suggest the intracellular targets for the molecules are putative α-carbonic and γ-carbonic anhydrases, and homology modeling and molecular dynamics simulations were performed. Together, this study presents potential anti-VRE therapeutic options to provide alternatives for problematic VRE infections.
Co, Ni, Cu, Zn, Hg) and metalloids from group 13-16 of the periodic table (e.g., Al, Ga, As, Sn, Sb, Pb, Bi) have increasingly Copper (Cu) and its alloys have been shown to eradicate a wide range of multidrug-resistant microbes upon direct contact. In this study, a facile one-step laser texturing (LT) process is demonstrated to effectively enhance the bactericidal properties of copper surfaces via concurrent selective modification of surface topography and chemistry of laser textured copper (LT-Cu). Surface morphology and elemental composition are analyzed via field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDX), and Raman spectroscopy. Surface area and pore size of LT-Cu is determined by Barrett-Joyner-Halenda (BJH) and Brunauer-Emmett-Teller (BET) analysis. It reveals direct formation of mesoporous structures with higher surface oxide (Cu 2 O and CuO), which provide a highly stable superhydrophilic property to the LT-Cu surfaces. The antibacterial properties of LT-Cu are tested against pathogenic bacterial strains with different concentrations including Pseudomonas aeruginosa, and methicillinresistant Staphylococcus aureus (MRSA USA300) at 10 5 CFU mL −1 , and Escherichia coli and Staphylococcus aureus at high bacterial concentrations of 10 8 CFU mL −1 using standard contact killing tests. The analysis shows that LT-Cu needs 40, 90, 60, and 120 min to completely eradicate the respective bacterial strain. The LT-Cu causes membrane damage to the bacterial cells immediately after exposure. Furthermore, the biocompatibility of LT-Cu is investigated by in vitro immune-staining assays with mammary stromal fibroblasts and T4-2 cells.
Ever since the discovery of vaccines, many deadly diseases have been contained worldwide, ultimately culminating in the eradication of smallpox and polio, which represented significant medical achievements in human health. However, this does not account for the threat influenza poses on public health. The currently licensed seasonal influenza vaccines primarily confer excellent strain-specific protection. In addition to the seasonal influenza viruses, the emergence and spread of avian influenza pandemic viruses such as H5N1, H7N9, H7N7, and H9N2 to humans have highlighted the urgent need to adopt a new global preparedness for an influenza pandemic. It is vital to explore new strategies for the development of effective vaccines for pandemic and seasonal influenza viruses. The new vaccine approaches should provide durable and broad protection with the capability of large-scale vaccine production within a short time. The adenoviral (Ad) vector-based vaccine platform offers a robust egg-independent production system for manufacturing large numbers of influenza vaccines inexpensively in a short timeframe. In this review, we discuss the progress in the development of Ad vector-based influenza vaccines and their potential in designing a universal influenza vaccine.
Neisseria gonorrhoeae is an urgent threat to public health in the United States and around the world. Many of the current classes of antibiotics to treat N. gonorrhoeae infection are quickly becoming obsolete due to increased rates of resistance. Thus, there is a critical need for alternative antimicrobial targets and new chemical entities. Our team has repurposed the FDA-approved carbonic anhydrase inhibitor scaffold of acetazolamide to target N. gonorrhoeae and the bacteria's essential carbonic anhydrase, NgCA. This study established both structure-activity and structureproperty relationships that contribute to both antimicrobial activity and NgCA activity. This ultimately led to molecules 20 and 23, which displayed minimum inhibitory concentration values as low as 0.25 μg/mL equating to an 8-to 16-fold improvement in anti-gonococcal activity compared to acetazolamide. These analogs were determined to be bacteriostatic against the
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