Ageing is a fundamental, unsolved mystery in biology. DAF-16, a FOXO-family transcription factor, influences the rate of ageing of Caenorhabditis elegans in response to insulin/insulin-like growth factor 1 (IGF-I) signalling. Using DNA microarray analysis, we have found that DAF-16 affects expression of a set of genes during early adulthood, the time at which this pathway is known to control ageing. Here we find that many of these genes influence the ageing process. The insulin/IGF-I pathway functions cell non-autonomously to regulate lifespan, and our findings suggest that it signals other cells, at least in part, by feedback regulation of an insulin/IGF-I homologue. Furthermore, our findings suggest that the insulin/IGF-I pathway ultimately exerts its effect on lifespan by upregulating a wide variety of genes, including cellular stress-response, antimicrobial and metabolic genes, and by downregulating specific life-shortening genes.

/pdf/genes-that-act-downstream-of-daf-16-to-influence-the-5eks7b6cw6.pdf

Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans

Summary: Treatment of infectious diseases becomes more challenging with each passing year. This is especially true for infections caused by the opportunistic pathogen Pseudomonas aeruginosa, with its ability to rapidly develop resistance to multiple classes of antibiotics. Although the import of resistance mechanisms on mobile genetic elements is always a concern, the most difficult challenge we face with P. aeruginosa is its ability to rapidly develop resistance during the course of treating an infection. The chromosomally encoded AmpC cephalosporinase, the outer membrane porin OprD, and the multidrug efflux pumps are particularly relevant to this therapeutic challenge. The discussion presented in this review highlights the clinical significance of these chromosomally encoded resistance mechanisms, as well as the complex mechanisms/pathways by which P. aeruginosa regulates their expression. Although a great deal of knowledge has been gained toward understanding the regulation of AmpC, OprD, and efflux pumps in P. aeruginosa, it is clear that we have much to learn about how this resourceful pathogen coregulates different resistance mechanisms to overcome the antibacterial challenges it faces.

Antibacterial-Resistant Pseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance Mechanisms

The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles. Areas addressed include mechanisms underlying this resistance, improved methods to detect resistance when it occurs, alternate options for the treatment of infections caused by resistant organisms, and strategies to prevent and control the emergence and spread of resistance. In this review, the mode of action of antifungals and their mechanisms of resistance are discussed. Additionally, an attempt is made to discuss the correlation between fungal and bacterial resistance. Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target. Although the comparison between the mechanisms of resistance to antifungals and antibacterials is necessarily limited by several factors defined in the review, a correlation between the two exists. For example, modification of enzymes which serve as targets for antimicrobial action and the involvement of membrane pumps in the extrusion of drugs are well characterized in both the eukaryotic and prokaryotic cells.

Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance

Root-secreted chemicals mediate multi-partite interactions in the rhizosphere, where plant roots continually respond to and alter their immediate environment. Increasing evidence suggests that root exudates initiate and modulate dialogue between roots and soil microbes. For example, root exudates serve as signals that initiate symbiosis with rhizobia and mycorrhizal fungi. In addition, root exudates maintain and support a highly specific diversity of microbes in the rhizosphere of a given particular plant species, thus suggesting a close evolutionary link. In this review, we focus mainly on compiling the information available on the regulation and mechanisms of root exudation processes, and provide some ideas related to the evolutionary role of root exudates in shaping soil microbial communities.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-3040.2009.01926.x

Regulation and function of root exudates.

In the past decade, the frequency of diagnosed fungal infections has risen sharply due to several factors, including the increase in the number of immunosuppressed patients resulting from the AIDS epidemic and treatments during and after organ and bone marrow transplants. Linked with the increase in fungal infections is a recent increase in the frequency with which these infections are recalcitrant to standard antifungal therapy. This review summarizes the factors that contribute to antifungal drug resistance on three levels: (i) clinical factors that result in the inability to successfully treat refractory disease; (ii) cellular factors associated with a resistant fungal strain; and (iii) molecular factors that are ultimately responsible for the resistance phenotype in the cell. Many of the clinical factors that contribute to resistance are associated with the immune status of the patient, with the pharmacology of the drugs, or with the degree or type of fungal infection present. At a cellular level, antifungal drug resistance can be the result of replacement of a susceptible strain with a more resistant strain or species or the alteration of an endogenous strain (by mutation or gene expression) to a resistant phenotype. The molecular mechanisms of resistance that have been identified to date in Candida albicans include overexpression of two types of efflux pumps, overexpression or mutation of the target enzyme, and alteration of other enzymes in the same biosynthetic pathway as the target enzyme. Since the study of antifungal drug resistance is relatively new, other factors that may also contribute to resistance are discussed.

Clinical, cellular, and molecular factors that contribute to antifungal drug resistance.

By functional complementation of a PDR5 null mutant of Saccharomyces cerevisiae, we have cloned and sequenced the multidrug-resistance gene CDR1 of Candida albicans. Transformation by CDR1 of a PDR5-disrupted host hypersensitive to cycloheximide and chloramphenicol resulted in resistance to cycloheximide, chloramphenicol and other drugs, such as the antifungal miconazole, with collateral hypersensitivity to oligomycin, nystatin and 2,4 dinitrophenol. Our results also demonstrate the presence of several PDR5 complementing genes in C. albicans, displaying multidrug-resistance patterns different from PDR5 and CDR1. The nucleotide sequence of CDR1 revealed that, like PDR5, it encodes a putative membrane pump belonging to the ABC (ATP-binding cassette) superfamily. CDR1 encodes a 1501-residue protein of 169.9 kDa whose predicted structural organization is characterized by two homologous halves, each comprising a hydrophobic region with a set of six transmembrane stretches, preceded by a hydrophilic nucleotide binding fold.

Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungals.

PDR5, a novel yeast multidrug resistance conferring transporter controlled by the transcription regulator PDR1.

http://www.facm.ucl.ac.be/Full-texts-FACM/Vanbambeke-2000-1.pdf

Antibiotic efflux pumps.

http://derisilab.ucsf.edu/pdfs/DeRisi_FEBSLetts00.pdf

Genome microarray analysis of transcriptional activation in multidrug resistance yeast mutants

This minireview describes a network of genes involved in multiple drug resistance of the yeast S. cerevisiae. The transcription regulators, PDR1, PDR3, PDR7, and PDR9 control the expression of the gene PDR5, encoding a membrane protein of the ATP-binding-cassette superfamily and functioning as a drug extrusion pump. Next to PDR5, several other target genes, encoding membrane pumps of the ABC type, such as SNQ2, STE6, PDR10, PDR11, YOR1, but also other membrane-associated (such as GAS1, D4405) or soluble proteins (such as G3PD), involved or not in multidrug resistance, are found to be controlled by PDR1. On another side, the PDR3 regulator participates with its homolog PDR1 to co- and auto-regulation circuits of yeast multidrug resistance.

Elisabetta Balzi

Papers

Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungals.

PDR5, a novel yeast multidrug resistance conferring transporter controlled by the transcription regulator PDR1.

Antibiotic efflux pumps.

Genome microarray analysis of transcriptional activation in multidrug resistance yeast mutants

Yeast multidrug resistance: The PDR network