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1.  Structure and function of bacteriophage T4 
Future microbiology  2014;9:1319-1327.
Bacteriophage T4 is the most well-studied member of Myoviridae, the most complex family of tailed phages. T4 assembly is divided into three independent pathways: the head, the tail and the long tail fibers. The prolate head encapsidates a 172 kbp concatemeric dsDNA genome. The 925 Å-long tail is surrounded by the contractile sheath and ends with a hexagonal baseplate. Six long tail fibers are attached to the baseplate’s periphery and are the host cell’s recognition sensors. The sheath and the baseplate undergo large conformational changes during infection. X-ray crystallography and cryo-electron microscopy have provided structural information on protein–protein and protein–nucleic acid interactions that regulate conformational changes during assembly and infection of Escherichia coli cells.
PMCID: PMC4275845  PMID: 25517898
assembly; bacteriophage T4; baseplate; contractile tail; genome packaging; T4 infection
3.  Predatory prokaryotes wage war against eye infections 
Future microbiology  2014;9(4):429-432.
PMCID: PMC4467539  PMID: 24810340
antibiotic resistance; antimicrobial; Bdellovibrio bacteriovorus; conjunctivitis; Micavibrio aeruginosavorus; predatory bacteria; topical therapy
4.  Biofilms in periprosthetic orthopedic infections 
Future microbiology  2014;9(8):987-1007.
As the number of total joint arthroplasty and internal fixation procedures continues to rise, the threat of infection following surgery has significant clinical implications. These infections may have highly morbid consequences to patients, who often endure additional surgeries and lengthy exposures to systemic antibiotics, neither of which are guaranteed to resolve the infection. Of particular concern is the threat of bacterial biofilm development, since biofilm-mediated infections are difficult to diagnose and effective treatments are lacking. Developing therapeutic strategies have targeted mechanisms of biofilm formation and the means by which these bacteria communicate with each other to take on specialized roles such as persister cells within the biofilm. In addition, prevention of infection through novel coatings for prostheses and the local delivery of high concentrations of antibiotics by absorbable carriers has shown promise in laboratory and animal studies. Biofilm development, especially in an arthoplasty environment, and future diagnostic and treatment options are discussed.
PMCID: PMC4407677  PMID: 25302955
antibiotic resistance; arthroplasty; biofilm; coating; infection; planktonic; prosthesis; treatment
5.  Recent insights into Pasteurella multocida toxin and other G-protein-modulating bacterial toxins 
Future microbiology  2010;5(8):1185-1201.
Over the past few decades, our understanding of the bacterial protein toxins that modulate G proteins has advanced tremendously through extensive biochemical and structural analyses. This article provides an updated survey of the various toxins that target G proteins, ending with a focus on recent mechanistic insights in our understanding of the deamidating toxin family. The dermonecrotic toxin from Pasteurella multocida (PMT) was recently added to the list of toxins that disrupt G-protein signal transduction through selective deamidation of their targets. The C3 deamidase domain of PMT has no sequence similarity to the deamidase domains of the dermonecrotic toxins from Escherichia coli (cytotoxic necrotizing factor (CNF)1-3), Yersinia (CNFY) and Bordetella (dermonecrotic toxin). The structure of PMT-C3 belongs to a family of transglutaminase-like proteins, with active site Cys–His–Asp catalytic triads distinct from E. coli CNF1.
PMCID: PMC4407829  PMID: 20722598
cysteine protease; cytotoxic necrotizing factor; deamidation; dermonecrotic toxin; GTPase; heterotrimeric G proteins; Pasteurella multocida toxin; signal transduction; transglutamination
6.  Antifungal drug discovery: the process and outcomes 
Future microbiology  2014;9(6):791-805.
New data suggest that the global incidence of several types of fungal diseases have traditionally been under-documented. Of these, mortality caused by invasive fungal infections remains disturbingly high, equal to or exceeding deaths caused by drug-resistant tuberculosis and malaria. It is clear that basic research on new antifungal drugs, vaccines and diagnostic tools is needed. In this review, we focus upon antifungal drug discovery including in vitro assays, compound libraries and approaches to target identification. Genome mining has made it possible to identify fungal-specific targets; however, new compounds to these targets are apparently not in the antimicrobial pipeline. We suggest that ‘repurposing’ compounds (off patent) might be a more immediate starting point. Furthermore, we examine the dogma on antifungal discovery and suggest that a major thrust in technologies such as structural biology, homology modeling and virtual imaging is needed to drive discovery.
PMCID: PMC4144029  PMID: 25046525
antifungals; compound libraries; discovery; drug targets; repurposing
7.  [No title available] 
PMCID: PMC4296029  PMID: 21366420
8.  [No title available] 
PMCID: PMC4294706  PMID: 24571070
9.  Vesicular transport systems in fungi 
Future microbiology  2011;6(11):1371-1381.
Canonical and unconventional mechanisms of secretion in many eukaryotic cells are relatively well known. In contrast to the situation in animal cells, mechanisms of secretion in fungi must include the capacity for trans-cell wall passage of macromolecules to the extracellular space. Although these mechanisms remain somewhat elusive, several studies in recent years have suggested that vesicular transport is required for trans-cell wall secretion of large molecules. Several fungal molecules, including proteins, lipids, polysaccharides and pigments, are released to the extracellular space in vesicles. In pathogenic fungi, a number of these vesicular components are associated with fungal virulence. Indeed, extracellular vesicles produced by fungi can interfere with the immunomodulatory activity of host cells. Fungal vesicles share many functional aspects with mammalian exosomes and extracellular vesicles produced by bacteria, plants and protozoa, but their cellular origin remains unknown. Here, we discuss the involvement of vesicular transport systems in fungal physiology and pathogenesis, making parallels with the mammalian, bacterial, protozoan and plant cell literature.
PMCID: PMC4286297  PMID: 22082294
Cryptococcus neoformans; extracellular vesicles; fungal pathogens; secretion
10.  Towards an understanding of the role of Clostridium perfringens toxins in human and animal disease 
Future microbiology  2014;9(3):361-377.
Clostridium perfringens uses its arsenal of >16 toxins to cause histotoxic and intestinal infections in humans and animals. It has been unclear why this bacterium produces so many different toxins, especially since many target the plasma membrane of host cells. However, it is now established that C. perfringens uses chromosomally encoded alpha toxin (a phospholipase C) and perfringolysin O (a pore-forming toxin) during histotoxic infections. In contrast, this bacterium causes intestinal disease by employing toxins encoded by mobile genetic elements, including C. perfringens enterotoxin, necrotic enteritis toxin B-like, epsilon toxin and beta toxin. Like perfringolysin O, the toxins with established roles in intestinal disease form membrane pores. However, the intestinal disease-associated toxins vary in their target specificity, when they are produced (sporulation vs vegetative growth), and in their sensitivity to intestinal proteases. Producing many toxins with diverse characteristics likely imparts virulence flexibility to C. perfringens so it can cause an array of diseases.
PMCID: PMC4155746  PMID: 24762309
animal disease; avian necrotic enteritis; Clostridium perfringens; enterocolitis; enterotoxemia; food poisoning; gas gangrene; human disease; toxins
11.  Elucidating the role of T cells in protection against and pathogenesis of dengue virus infections 
Future microbiology  2014;9(3):411-425.
Dengue viruses (DENV) cause significantly more human disease than any other arbovirus, with hundreds of thousands of cases leading to severe disease in thousands annually. Antibodies and T cells induced by primary infection with DENV have the potential for both positive (protective) and negative (pathological) effects during subsequent DENV infections. In this review, we summarize studies that have examined T-cell responses in humans following natural infection and vaccination. We discuss studies that support a role for T cells in protection against and those that support a role for the involvement of T cells in the pathogenesis of severe disease. The mechanisms that lead to severe disease are complex, and T-cell responses are an important component that needs to be further evaluated for the development of safe and efficacious DENV vaccines.
PMCID: PMC4113002  PMID: 24762312
dengue; immune response; immunopathology; nonstructural proteins; primary infection; secondary infection; T lymphocyte; vaccine
12.  Master manipulators: an update on Legionella pneumophila Icm/Dot translocated substrates and their host targets 
Future microbiology  2014;9(3):343-359.
Macrophages are the front line of immune defense against invading microbes. Microbes, however, have evolved numerous and diverse mechanisms to thwart these host immune defenses and thrive intracellularly. Legionella pneumophila, a Gram-negative pathogen of amoebal and mammalian phagocytes, is one such microbe. In humans, it causes a potentially fatal pneumonia referred to as Legionnaires' disease. Armed with the Icm/Dot type IV secretion system, which is required for virulence, and approximately 300 translocated proteins, Legionella is able to enter host cells, direct the biogenesis of its own vacuolar compartment, and establish a replicative niche, where it grows to high levels before lysing the host cell. Efforts to understand the pathogenesis of this bacterium have focused on characterizing the molecular activities of its many effectors. In this article, we highlight recent strides that have been made in understanding how Legionella effectors mediate host-pathogen interactions.
PMCID: PMC4148032  PMID: 24762308
autophagy; intracellular pathogen; Legionella pneumophila; macrophages; protein translocation
13.  Oncolytic Newcastle Disease Virus for cancer therapy: old challenges and new directions 
Future microbiology  2012;7(3):347-367.
Newcastle Disease Virus (NDV) is an avian paramyxovirus, which has been demonstrated to possess significant oncolytic activity against mammalian cancers. This review summarizes the research leading to the elucidation of the mechanisms of NDV-mediated oncolysis as well as the development of novel oncolytic agents through the use of genetic engineering. Clinical trials utilizing NDV strains and NDV-based autologous tumor cell vaccines will expand our knowledge of these novel anti-cancer strategies and will ultimately result in the successful use of the virus in the clinical setting.
PMCID: PMC4241685  PMID: 22393889
NDV; oncolytic; immunotherapy; apoptosis; interferon; cancer
14.  Invasive fungal infections in solid organ transplant recipients 
Future microbiology  2012;7(5):639-655.
Invasive fungal infections are a major problem in solid organ transplant (SOT) recipients. Overall, the most common fungal infection in SOT is candidiasis, followed by aspergillosis and cryptococcosis, except in lung transplant recipients, where aspergillosis is most common. Development of invasive disease hinges on the interplay between host factors (e.g., integrity of anatomical barriers, innate and acquired immunity) and fungal factors (e.g., exposure, virulence and resistance to prophylaxis). In this article, we describe the epidemiology and clinical features of the most common fungal infections in organ transplantation. Within this context, we review recent advances in diagnostic modalities and antifungal chemotherapy, and their impact on evolving prophylaxis and treatment paradigms.
PMCID: PMC4222063  PMID: 22568718
antifungal; aspergillosis; candidiasis; cryptococcosis; fungal; galactomannan; kidney transplant; liver transplant; lung transplant; transplant
15.  Regulation of the life cycle of HPVs by differentiation and the DNA damage response 
Future microbiology  2013;8:1547-1557.
HPVs are the causative agents of cervical and other anogenital cancers. HPVs infect stratified epithelia and link their productive life cycles to cellular differentiation. Low levels of viral genomes are stably maintained in undifferentiated cells and productive replication or amplification is restricted to differentiated suprabasal cells. Amplification is dependent on the activation of the ATM DNA damage factors that are recruited to viral replication centers and inhibition of this pathway blocks productive replication. The STAT-5 protein appears to play a critical role in mediating activation of the ATM pathway in HPV-positive cells. While HPVs need to activate the DNA damage pathway for replication, cervical cancers contain many genomic alterations suggesting that this pathway is circumvented during progression to malignancy.
PMCID: PMC3951404  PMID: 24266355
amplification; ATM; CHK2; differentiation; DNA damage; papillomaviruses; replication foci; STAT-5
16.  Mechanisms of Candida biofilm drug resistance 
Future microbiology  2013;8(10):10.2217/fmb.13.101.
Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, β-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases.
PMCID: PMC3859465  PMID: 24059922
antifungal resistance; biofilm; calcineurin; Candida; efflux pumps; extracellular matrix; glucan; persister cells
17.  Recent molecular insights into rickettsial pathogenesis and immunity 
Future microbiology  2013;8(10):1265-1288.
Human infections with arthropod-borne Rickettsia species remain a major global health issue, causing significant morbidity and mortality. Epidemic typhus due to Rickettsia prowazekii has an established reputation as the ‘scourge of armies’, and as a major determinant of significant ‘historical turning points’. No suitable vaccines for human use are currently available to prevent rickettsial diseases. The unique lifestyle features of rickettsiae include obligate intracellular parasitism, intracytoplasmic niche within the host cell, predilection for infection of microvascular endothelium in mammalian hosts, association with arthropods and the tendency for genomic reduction. The fundamental research in the field of Rickettsiology has witnessed significant recent progress in the areas of pathogen adhesion/invasion and host immune responses, as well as the genomics, proteomics, metabolomics, phylogenetics, motility and molecular manipulation of important rickettsial pathogens. The focus of this review article is to capture a snapshot of the latest developments pertaining to the mechanisms of rickettsial pathogenesis and immunity.
PMCID: PMC3923375  PMID: 24059918
endothelium; genomics; innate immunity; metabolomics; pathogenesis; plasmids; proteomics; Rickettsia; spotted fever; typhus
18.  Genetics of Coxiella burnetii: on the path of specialization 
Future microbiology  2011;6(11):1297-1314.
Coxiella burnetii is an extremely infectious, zoonotic agent that causes Q fever in humans. With the exception of New Zealand, the bacterium is distributed worldwide. Coxiella is classified as a select agent based on its past and potential use as a bioweapon and its threat to public health. Despite decades of research, we know relatively little regarding Coxiella’s molecular pathogenesis, and a vaccine is not widely available. This article briefly reviews the unusual genetics of C. burnetii; a pathogen that retains telltale genetic mementos collected over the course of its evolutionary path from a free-living bacterium to an obligate intracellular parasite of eukaryotic host cell phagosomes. Understanding why these genetic elements are maintained may help us better understand the biology of this fascinating pathogen.
PMCID: PMC4104754  PMID: 22082290
chromosome; Coxiella; genome reduction; genomics; genotype; plasmids; Q fever; selfish genetic elements
19.  Radioimmunotherapy of Cryptococcus neoformans spares bystander mammalian cells 
Future microbiology  2013;8(9):1081-1089.
Previously, we showed that radioimmunotherapy (RIT) for cryptococcal infections using radioactively labeled antibodies recognizing the cryptococcal capsule reduced fungal burden and prolonged survival of mice infected with Cryptococcus neoformans. Here, we investigate the effects of RIT on bystander mammalian cells.
Materials & methods
Heat-killed C. neoformans bound to anticapsular antibodies, unlabeled or labeled with the β-emitter rhenium-188 (16.9-h half-life) or the α-emitter bismuth-213 (46-min half-life), was incubated with macrophage-like J774.16 cells or epithelial-like Chinese hamster ovary cells. Lactate dehydrogenase activity, crystal violet uptake, reduction of tetrazolium dye (2,3)-bis-(2-methoxy-4-nitro-5-sulfenyl)-(2H)-terazolium-5-carboxanilide and nitric oxide production were measured.
The J774.16 and Chinese hamster ovary cells maintained membrane integrity, viability and metabolic activity following exposure to radiolabeled C. neoformans.
RIT of C. neoformans is a selective therapy with minimal effects on host cells and these results are consistent with observations that RIT-treated mice with cryptococcal infection lacked RIT-related pathological changes in lungs and brain tissues.
PMCID: PMC3932562  PMID: 24020737
bystander effects; Cryptococcus neoformans; fungal infection; NO production; particulate radiation; radioimmunotherapy
20.  Bacterial oncogenesis in the colon 
Future microbiology  2013;8(4):445-460.
The human colon plays host to a diverse and metabolically complex community of microorganisms. While the colonic microbiome has been suggested to contribute to the development of colorectal cancer (CRC), a definitive link has not been made. The role in which the colon microflora could contribute to the initiation and/or progression of CRC is explored in this review. Potential mechanisms of bacterial oncogenesis are presented, along with lines of evidence derived from animal models of microbially induced CRC. Particular focus is given to the oncogenic capabilities of enterotoxigenic Bacteroides fragilis. Recent progress in defining the microbiome of CRC in the human population is evaluated, and the future challenges of linking specific etiologic agents to CRC are emphasized.
PMCID: PMC4052711  PMID: 23534358
bacterial toxin; chronic inflammation; colonic microbiome; colorectal cancer; genotoxins; oncogenesis
21.  Genetic variation in Chlamydia trachomatis and their hosts: impact on disease severity and tissue tropism 
Future microbiology  2013;8(9):1129-1146.
Chlamydia trachomatis infections are a global health problem. This obligate intracellular bacterial pathogen comprises lymphogranuloma venereum (L1–L3), ocular (A–C) and genital (D–K) serovars. Although genetically similar, each serovar group differs in disease severity and tissue tropism through mechanisms that are not well understood. It is clear that host genetic differences also play a role in chlamydial disease outcome and key host polymorphisms are beginning to emerge from both human and experimental animal studies. In this review, we will highlight pathogen and host genes that link genetic diversity, disease severity and tissue tropism. We will also use this information to provide new insights that may be helpful in developing improved management strategies for these important pathogens.
PMCID: PMC4009991  PMID: 24020741
Chlamydia trachomatis; disease severity; gene polymorphisms; genetic variation; genital tract infections; tissue tropism
22.  Progress in targeting cell envelope biogenesis in Mycobacterium tuberculosis 
Future microbiology  2013;8(7):10.2217/fmb.13.52.
Most of the newly discovered compounds showing promise for the treatment of TB, notably multidrug-resistant TB, inhibit aspects of Mycobacterium tuberculosis cell envelope metabolism. This review reflects on the evolution of the knowledge that many of the front-line and emerging products inhibit aspects of cell envelope metabolism and in the process are bactericidal not only against actively replicating M. tuberculosis, but contrary to earlier impressions, are effective against latent forms of the disease. While mycolic acid and arabinogalactan synthesis are still primary targets of existing and new drugs, peptidoglycan synthesis, transport mechanisms and the synthesis of the decaprenyl-phosphate carrier lipid all show considerable promise as targets for new products, older drugs and new combinations. The advantages of whole cell- versus target-based screening in the perpetual search for new targets and products to counter multidrug-resistant TB are discussed.
PMCID: PMC3867987  PMID: 23841633
antibiotic; arabinogalactan; cell envelope; Mycobacterium; mycolic acids; peptidoglycan; tuberculosis
23.  Developing insights into the mechanisms of evolution of bacterial pathogens from whole-genome sequences 
Future microbiology  2012;7(11):1283-1296.
Evolution of bacterial pathogen populations has been detected in a variety of ways including phenotypic tests, such as metabolic activity, reaction to antisera and drug resistance and genotypic tests that measure variation in chromosome structure, repetitive loci and individual gene sequences. While informative, these methods only capture a small subset of the total variation and, therefore, have limited resolution. Advances in sequencing technologies have made it feasible to capture whole-genome sequence variation for each sample under study, providing the potential to detect all changes at all positions in the genome from single nucleotide changes to large-scale insertions and deletions. In this review, we focus on recent work that has applied this powerful new approach and summarize some of the advances that this has brought in our understanding of the details of how bacterial pathogens evolve.
PMCID: PMC3996552  PMID: 23075447
bacteria; evolution; genome sequencing; horizontal gene transfer; mutation; recombination; selection
24.  Pharmacology of polymyxins: new insights into an ‘old’ class of antibiotics 
Future microbiology  2013;8(6):10.2217/fmb.13.39.
Increasing antibiotic resistance in Gram-negative bacteria, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, presents a global medical challenge. No new antibiotics will be available for these ‘superbugs’ in the near future due to the dry antibiotic discovery pipeline. Colistin and polymyxin B are increasingly used as the last-line therapeutic options for treatment of infections caused by multidrug-resistant Gram-negative bacteria. This article surveys the significant progress over the last decade in understanding polymyxin chemistry, mechanisms of antibacterial activity and resistance, structure–activity relationships and pharmacokinetics/pharmacodynamics. In the ‘Bad Bugs, No Drugs’ era, we must pursue structure–activity relationship-based approaches to develop novel polymyxin-like lipopeptides targeting polymyxin-resistant Gram-negative ‘superbugs’. Before new antibiotics become available, we must optimize the clinical use of polymyxins through the application of pharmacokinetic/pharmacodynamic principles, thereby minimizing the development of resistance.
PMCID: PMC3852176  PMID: 23701329
colistin; lipid A; lipopolysaccharide; pharmacokinetic/pharmacodynamic; polymyxin; resistance; structure–activity relationship
25.  The ferric uptake regulator of Helicobacter pylori: a critical player in the battle for iron and colonization of the stomach 
Future microbiology  2013;8(6):10.2217/fmb.13.43.
Helicobacter pylori is arguably one of the most successful pathogens; it colonizes the stomachs of more than half of the human population. Colonization and persistence in such an inhospitable niche requires the presence of exquisite adaptive mechanisms. One of the proteins that contributes significantly to the remarkable adaptability of H. pylori is the ferric uptake regulator (Fur), which functions as a master regulator of gene expression. In addition to genes directly related to iron homeostasis, Fur controls expression of several enzymes that play a central role in metabolism and energy production. The absence of Fur leads to severe H. pylori colonization defects and, accordingly, several Fur-regulated genes have been shown to be essential for colonization. Moreover, proteins encoded by Fur-regulated genes have a strong impact on redox homeostasis in the stomach and are major determinants of inflammation. In this review, we discuss the main roles of Fur in the biology of H. pylori and highlight the importance of this regulatory protein in the infectious process.
PMCID: PMC3852439  PMID: 23701330
colonization; ferric uptake regulator; gastric cancer; Helicobacter pylori; inflammation; iron; iron acquisition; iron metabolism; virulence

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