Optimization of globomycin analogs as novel gram-negative antibiotics
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Authors: Garland, Keira; Pantua, Homer; Braun, Marie-Gabrielle; Burdick, Daniel J.; Castanedo, Georgette M.; Chen, Yi-Chen; Cheng, Yun-Xing; Cheong, Jonathan; Daniels, Blake; Deshmukh, Gauri; Fu, Yuhong; Gibbons, Paul; Gloor, Susan L.; Hua, Rongbao; Labadie, Sharada; Liu, Xiongcai; Pastor, Richard; Stivala, Craig; Xu, Min; Xu, Yiming; Zheng, Hao; Kapadia, Sharookh B.; Hanan, Emily J.
Discovery of novel classes of Gram-negative antibiotics with activity against multi-drug resistant infections is a critical unmet need. As an essential member of the lipoprotein biosynthetic pathway, lipoprotein signal peptidase II (LspA) is an attractive target for antibacterial drug discovery, with the natural product inhibitor globomycin offering a modestly-active starting point. Informed by structure-based design, the globomycin depsipeptide was optimized to improve activity against E. coli. Backbone modifications, together with adjustment of physicochemical properties, afforded potent compounds with good in vivo pharmacokinetic profiles. Optimized compounds such as 51 (E. coli MIC 3.1 mu M) and 61 (E. coli MIC 0.78 mu M) demonstrate broad spectrum activity against gram-negative pathogens and may provide opportunities for future antibiotic discovery.
Biofilm modelling on the contact lenses and comparison of the in vitro activities of multipurpose lens solutions and antibiotics
Authors: Dosler, Sibel; Hacioglu, Mayram; Yilmaz, Fatima Nur; Oyardi, Oziem
During the contact lens (CL) usage, microbial adhesion and biofilm formation are crucial threats for eye health due to the development of mature biofilms on CL surfaces associated with serious eye infections such as keratitis. For CL related eye infections, multi drug resistant Pseudomonas aeruginosa or Staphylococcus aureus (especially MRSA) and Candida albicans are the most common infectious bacteria and yeast, respectively. In this study, CL biofilm models were created by comparing them to reveal the differences on specific conditions. Then the anti-biofilm activities of some commercially available multipurpose CL solutions (MPSs) and antibiotic eye drops against mature biofilms of S. aureus, P. aeruginosa, and C. albicans standard and clinical strains were determined by the time killing curve (TKC) method at 6, 24 and 48 h. According to the biofilm formation models, the optimal biofilms occurred in a mixture of bovine serum albumin (20% v/v) and lysozyme (2 g/L) diluted in PBS at 37 degrees C for 24 h, without shaking. When we compared the CL types under the same conditions, the strongest biofilms according to their cell density, were formed on Pure Vision >= Softens 38 > Acuve 2 similar to Softens Toric CLs. When we compared the used CLs with the new ones, a significant increase at the density of biofilms on the used CLs was observed. The most active MPS against P. aeruginosa and S. aureus biofilms at 24 h was Opti-Free followed by Bio-True and Renu according to the TKC analyses. In addition, the most active MPS against C. albicans was Renu followed by Opti-Free and Bio-True at 48 h. None of the MPSs showed 3 Log bactericidal/fungicidal activity, except for Opti-Free against S. aureus and P. aeruginosa biofilms during 6 h contact time. Moreover, all studied antibiotic eye drops were active against S. aureus and P. aeruginosa biofilms on CLs at 6 h and 24 h either directly or as 1/10 concentration, respectively. According to the results of the study, anti-biofilm activities of MPSs have changed depending on the chemical ingredients and contact times of MPSs, the type of infectious agent, and especially the CL type and usage time.