contributed equally to this workThe Ess1/Pin1 peptidyl-prolyl isomerase (PPIase) is thought to control mitosis by binding to cell cycle regulatory proteins and altering their activity. Here we isolate temperature-sensitive ess1 mutants and identify six multicopy suppressors that rescue their mitotic-lethal phenotype. None are cell cycle regulators. Instead, ®ve encode proteins involved in transcription that bind DNA, modify chromatin structure or are regulatory subunits of RNA polymerase II. A sixth suppressor, cyclophilin A, is a member of a distinct family of PPIases that are targets of immunosuppressive drugs. We show that the expression of some but not all genes is decreased in ess1 mutants, and that Ess1 interacts with the C-terminal domain (CTD) of RNA polymerase II in vitro and in vivo. The results forge a strong link between PPIases and the transcription machinery and suggest a new model for how Ess1/Pin1 controls mitosis. In this model, Ess1 binds and isomerizes the CTD of RNA polymerase II, thus altering its interaction with proteins required for transcription of essential cell cycle genes.

Antibacterial drug discovery and development has slowed considerably in recent years with novel classes discovered decades ago and regulatory approvals tougher to get. This article describes newer classes of antibacterial drugs introduced or approved after year 2000, their mechanisms of action/ resistance, improved analogs, spectrum of activity and clinical trials. It also discusses new compounds in development with novel mechanisms of action as well as novel unexploited bacterial targets and strategies which may pave the way for combating drug resistance and emerging pathogens in the 21 st century. Keywordsantibacterial; drug discovery; drug resistance Infectious diseases are one of the leading causes of death worldwide, especially in low and middle income (LMIC) countries where second line antibacterial drugs against resistant bacteria are generally unavailable or unaffordable. In upper income countries (UIC), the emergence of multi-drug resistance in both community and hospital acquired infections has outpaced development and delivery of new drugs to the clinic. Most recently, the emergence of carbapenem resistance among Klebsiella sp. and related Gram negative bacteria illustrates the magnitude of the problem, as these multi-drug resistant infections are associated with high mortality rates and few treatment options 1. While the market potential for new antibacterial drugs is estimated in the many billions of dollars 2 , the discovery pipelines of most major pharmaceutical companies run near empty. The paucity of new antibacterial drugs has led the Infectious Disease Society of America (IDSA) and others to call for action in rebuilding infrastructure and efforts to develop next generation drugs.Despite the many grim predictions of failure in combating infectious diseases in the future 3 , 4 , all is not lost, as several classes of new antibacterial compounds as well as derivatives of older therapeutics have emerged. In this review we examine some of these new antibacterial drugs that have recently been approved by the FDA (and EMEA) or are in late stages (phase II development or beyond) of the pipeline. These new drugs belong to the following classes of compounds that include: oxazolidinones, glycopeptides, ketolides, glycylcyclines, carbapenems and fluoroquinolones (Table 1). This article will describe in detail the mechanism of action (novelty), spectrum of activity, selected in vivo efficacy and mechanisms of resistance to these antibacterial drugs and also discusses briefly more new drugs in development (Table 2). We also have included unpublished information reported at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the Infectious Disease NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptSociety of America (IDSA) 46th Annual Meeting in 2008 and here after noted as ICAAC/ IDSA. In addition, we also explore novel strategies such as targeting host infection response pathways, anti-infective antibodies or the vitamin cofactors of...

Ess1 is a peptidyl-prolyl cis/trans isomerase (PPIase) that binds to the carboxy-terminal domain (CTD) of RNA polymerase II. Ess1 is thought to function by inducing conformational changes in the CTD that control the assembly of cofactor complexes on the transcription unit. Ess1 (also called Pin1) is highly conserved throughout the eukaryotic kingdom and is required for growth in some species, including the human fungal pathogen Candida albicans. Here we report the crystal structure of the C. albicansEss1 protein, determined at 1.6 A resolution. The structure reveals two domains, the WW and the isomerase domain, that have conformations essentially identical to those of human Pin1. However, the linker region that joins the two domains is quite different. In human Pin1, this linker is short and flexible, and part of it is unstructured. In contrast, the fungal Ess1 linker is highly ordered and contains a long alpha-helix. This structure results in a rigid juxtaposition of the WW and isomerase domains, in an orientation that is distinct from that observed in Pin1, and that eliminates a hydrophobic pocket between the domains that was implicated as the main substrate recognition site. These differences suggest distinct modes of interaction with long substrate molecules, such as the CTD of RNA polymerase II. We also show that C. albicans ess1(-)() mutants are attenuated for in vivo survival in mice. Together, these results suggest that CaEss1 might constitute a useful antifungal drug target, and that structural differences between the fungal and human enzymes could be exploited for drug design.