The allyl moiety of the immunosuppressive agent FK506 is structurally unique amongst polyketides and critical for its potent biological activity. Here, we detail the biosynthetic pathway to allylmalonyl-coenzyme A (CoA), from which the FK506 allyl group is derived, based on a comprehensive chemical, biochemical and genetic interrogation of three FK506 gene clusters. A discrete polyketide synthase (PKS) with noncanonical domain architecture presumably in coordination with the fatty acid synthase pathway of the host catalyzes a multi-step enzymatic reaction to allylmalonyl-CoA via trans-2-pentenyl-acyl carrier protein. Characterization of this discrete pathway facilitated the engineered biosynthesis of novel allyl group-modified FK506 analogs, namely 36-fluoro-FK520 and 36-methyl-FK506, the latter of which exhibits improved * slim@genotech.co.kr .* joonyoon@ewha.ac.kr . 8 These authors contributed equally to this work.

BackgroundBloodstream infection (BSI) is a significant cause of morbidity and mortality in liver transplant (LT) recipients. This study aimed to investigate the epidemiology and clinical features of post-transplant BSI in LT recipients.Materials and MethodsThe microbiology, frequency, and outcome of post-transplant BSI in the first year after LT were retrospectively analyzed in 222 consecutive patients who had received liver transplants at a single center between 2005 and 2011. The risk factors for post-transplant BSI and death were evaluated.ResultsDuring a 1-year period after LT, 112 episodes of BSI occurred in 64 of the 222 patients (28.8%). A total of 135 microorganisms were isolated from 112 BSI episodes including 18 polymicrobial episodes. The median time to BSI onset ranged from 8 days for Klebsiella pneumoniae to 101 days for enterococci, and the overall median for all microorganisms was 28 days. The most frequent pathogens were Enterobacteriaceae members (32.5%), enterococci (17.8%), yeasts (14.0%), Staphylococcus aureus (10.3%), and Acinetobacter baumannii (10.3%); most of them showed resistance to major antibiotics. The major sources of BSI were biliary tract (36.2%), abdominal and/or wound (28.1%), and intravascular catheter (18.5%) infections. The independent risk factors for post-transplant BSI were biliary complications (odds ratio [OR]: 2.91, 95% confidence interval [CI]: 1.29 to 6.59, P = 0.010) and longer hospitalization in the intensive care unit (OR: 1.04, 95% CI: 1.00 to 1.08, P < 0.001) after LT. BSI was an independent risk factor for death (hazard ratio [HR]: 3.92, 95% CI: 2.22 to 6.91, P < 0.001), with a poorer survival rate observed in patients with BSI than in those without BSI (1-year survival rate: 60.0% versus 89.5%, respectively, P < 0.001) after LT. The strongest predictors for death in patients with BSI were hepatocellular carcinoma (HR: 3.82, 95% CI: 1.57 to 9.32, P = 0.003), candidemia (HR: 3.71, 95% CI: 1.58 to 8.71, P = 0.003), polymicrobial bacteremia (HR: 3.18, 95% CI: 1.39 to 7.28, P = 0.006), and post-transplant hemodialysis (HR: 2.44, 95% CI: 1.02 to 5.84, P = 0.044).ConclusionsBSI was a frequent post-transplant complication, and most of the causative pathogens were multi-drug resistant. Biliary complications and BSIs resulting from biliary infection are major problems for LT recipients. The prevention of BSI and biliary complications is critical in improving prognosis in liver transplant recipients.

The OSI based on the double-pass system was correlated with the Scheimpflug-measured lens density, subjective lens grading, and CDE. The OSI may improve the preoperative evaluation of nuclear cataract and help predict phacodynamics in cataract surgery.