Diversity management has grown out of the need for organizations, agencies, and departments to address a changing workforce and other pervasive social pressures. An army of experts has emerged to meet this growing need, but frequently with questionable results. This paper highlights why diversity training is important and will become even more so, issues related to quality control of providers and services, what may go wrong within the context of providing diversity training programs, and the results in these situations for individuals and organizations.

The macrocyclic polyketides FK506, FK520, and rapamycin are potent immunosuppressants that prevent T-cell proliferation through initial binding to the immunophilin FKBP12. Analogs of these molecules are of considerable interest as therapeutics in both metastatic and inflammatory disease. For these polyketides the starter unit for chain assembly is (4 R ,5 R )-4,5-dihydroxycyclohex-1-enecarboxylic acid derived from the shikimate pathway. We show here that the first committed step in its formation is hydrolysis of chorismate to form (4 R ,5 R )-4,5-dihydroxycyclohexa-1,5-dienecarboxylic acid. This chorismatase activity is encoded by fkbO in the FK506 and FK520 biosynthetic gene clusters, and by rapK in the rapamycin gene cluster of Streptomyces hygroscopicus . Purified recombinant FkbO (from FK520) efficiently catalyzed the chorismatase reaction in vitro, as judged by HPLC-MS and NMR analysis. Complementation using fkbO from either the FK506 or the FK520 gene cluster of a strain of S. hygroscopicus specifically deleted in rapK (BIOT-4010) restored rapamycin production, as did supplementation with (4 R ,5 R )-4,5-dihydroxycyclohexa-1,5-dienecarboxylic acid. Although BIOT-4010 produced no rapamycin, it did produce low levels of BC325, a rapamycin analog containing a 3-hydroxybenzoate starter unit. This led us to identify the rapK homolog hyg5 as encoding a chorismatase/3-hydroxybenzoate synthase. Similar enzymes in other bacteria include the product of the bra8 gene from the pathway to the terpenoid natural product brasilicardin. Expression of either hyg5 or bra8 in BIOT-4010 led to increased levels of BC325. Also, purified Hyg5 catalyzed the predicted conversion of chorismate into 3-hydroxybenzoate. FkbO, RapK, Hyg5, and Bra8 are thus founder members of a previously unrecognized family of enzymes acting on chorismate.

Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30-to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC 50 s] of 0.070 M and 0.16 M in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F < 4%) and low solubility (<25 M), although the half-lives (t 1/2 ) of SfA and SfB in mouse blood after intravenous (i.v.) dosing were long (t 1/2 > 5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties.Hepatitis C virus (HCV) is a positive-strand RNA virus and is the major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (39). The World Health Organization (WHO) estimates that there are more than 170 million chronic carriers of HCV, which is approximately 3% of the world population (28,29). In developed countries, 50 to 76% of all cases of liver cancer and two-thirds of all liver transplants are due to chronic HCV infection (37).The current standard of care (SOC) involves subcutaneous injections of pegylated alpha-interferon (peg-IFN-␣) and oral dosing of the nonspecific antiviral drug ribavirin for a period of 24 to 48 weeks (9). Overall, response rates to the SOC depend upon the genotype and the pretreatment HCV RNA levels. Patients with genotypes 2 and 3 are more responsive to the SOC than patients infected with genotype 1 (particularly 1b) (25, 31). A significant number of HCV patients do not respond adequately to the SOC or cannot tolerate it due to side effects, leading to poor compliance and a sustained virological response (SVR) of about 50% (31).Direct-acting antiviral (DAA) drugs are being developed to target viral proteins, such as HCV NS5B polymerase or NS3 protease (35). One concern with the increased use of virustargeted agents is that, as was observed with HIV treatment, drug resistance emerges (47). However, compounds that target human proteins (i.e., cyclophilins), rather than viral targets, are also being developed, which should have higher hurdles for viral breakthrough and incidence of resistance duri...

A biosynthetic medicinal chemistry approach was applied to the optimization of the natural product Hsp90 inhibitor macbecin. By genetic engineering, mutants have been created to produce novel macbecin analogues including a nonquinone compound (5) that has significantly improved binding affinity to Hsp90 (Kd 3 nM vs 240 nM for macbecin) and reduced toxicity (MTD > or = 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.

Sangamides are amide derivatives of sanglifehrin A, a cyclophilin-binding polyketide natural product which is structurally distinct from cyclosporine A. Cyclosporine A is the starting point for the synthesis of cyclophilin inhibitors such as alisporivir, currently in development for the treatment of HCV infection. We report here initial results of the optimisation program which led to identification of the sangamides, compounds that exhibit significantly improved potential for the treatment of chronic HCV infection.