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Fungal Biofilm Resistance  [PDF]
Gordon Ramage,Ranjith Rajendran,Leighann Sherry,Craig Williams
International Journal of Microbiology , 2012, DOI: 10.1155/2012/528521
Abstract: Fungal biofilm infections have become increasingly recognised as a significant clinical problem. One of the major reasons behind this is the impact that these have upon treatment, as antifungal therapy often fails and surgical intervention is required. This places a large financial burden on health care providers. This paper aims to illustrate the importance of fungal biofilms, particularly Candida albicans, and discusses some of the key fungal biofilm resistance mechanisms that include, extracellular matrix (ECM), efflux pump activity, persisters, cell density, overexpression of drug targets, stress responses, and the general physiology of the cell. The paper demonstrates the multifaceted nature of fungal biofilm resistance, which encompasses some of the newest data and ideas in the field.
Fungal Biofilm Resistance  [PDF]
Gordon Ramage,Ranjith Rajendran,Leighann Sherry,Craig Williams
International Journal of Microbiology , 2012, DOI: 10.1155/2012/528521
Abstract: Fungal biofilm infections have become increasingly recognised as a significant clinical problem. One of the major reasons behind this is the impact that these have upon treatment, as antifungal therapy often fails and surgical intervention is required. This places a large financial burden on health care providers. This paper aims to illustrate the importance of fungal biofilms, particularly Candida albicans, and discusses some of the key fungal biofilm resistance mechanisms that include, extracellular matrix (ECM), efflux pump activity, persisters, cell density, overexpression of drug targets, stress responses, and the general physiology of the cell. The paper demonstrates the multifaceted nature of fungal biofilm resistance, which encompasses some of the newest data and ideas in the field. 1. Clinical Significance of Fungal Biofilms Fungi represent a significant burden of infection to the hospital population. The use of broad-spectrum antibiotics, parenteral nutrition, indwelling catheters, or the presence of immunosuppression, or disruption of mucosal barriers due to surgery, chemotherapy, and radiotherapy are among the most important predisposing factors for invasive fungal infection [1]. Candida bloodstream infection is the third most common cause of nosocomial bacteremia in patients requiring intensive care and the most common etiologic agent of fungal-related biofilm infection. C. albicans, a normal commensal of human mucosal surfaces and opportunistic pathogen in immunocompromised patients, is most frequently associated with biofilm formation. Indwelling medical devices, such as intravascular catheters, can become colonized with Candida spp. allowing the development of adherent biofilm structures from which cells can then detach and cause an acute fungemia and/or disseminated infection. It has recently been shown that the cells that detach from the biofilm have a greater association with mortality than equivalent planktonic yeasts [2]. These implant-associated infections are inherently difficult to resolve and may require both long-term antifungal therapy and the physical removal of the implant to control the infection. Other nonalbicans Candida species associated with biofilm formation and catheter-related bloodstream or device-related infections include C. glabrata, C. parapsilosis, C. dubliniensis, C. krusei, and C. tropicalis [3–5]. Yeasts and filamentous fungi biofilm-related infections have also been increasingly described [6], including Pneumocystis [7], Coccidioides [8], Aspergillus [9], Zygomycetes [10], Blastoschizomyces [11],
Hsp90 Governs Dispersion and Drug Resistance of Fungal Biofilms  [PDF]
Nicole Robbins equal contributor,Priya Uppuluri equal contributor,Jeniel Nett,Ranjith Rajendran,Gordon Ramage,Jose L. Lopez-Ribot,David Andes,Leah E. Cowen
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002257
Abstract: Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections.
The Hsp90 Co-Chaperone Sgt1 Governs Candida albicans Morphogenesis and Drug Resistance  [PDF]
Rebecca S. Shapiro, Aimee K. Zaas, Marisol Betancourt-Quiroz, John R. Perfect, Leah E. Cowen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044734
Abstract: The molecular chaperone Hsp90 orchestrates regulatory circuitry governing fungal morphogenesis, biofilm development, drug resistance, and virulence. Hsp90 functions in concert with co-chaperones to regulate stability and activation of client proteins, many of which are signal transducers. Here, we characterize the first Hsp90 co-chaperone in the leading human fungal pathogen, Candida albicans. We demonstrate that Sgt1 physically interacts with Hsp90, and that it governs C. albicans morphogenesis and drug resistance. Genetic depletion of Sgt1 phenocopies depletion of Hsp90, inducing yeast to filament morphogenesis and invasive growth. Sgt1 governs these traits by bridging two morphogenetic regulators: Hsp90 and the adenylyl cyclase of the cAMP-PKA signaling cascade, Cyr1. Sgt1 physically interacts with Cyr1, and depletion of either Sgt1 or Hsp90 activates cAMP-PKA signaling, revealing the elusive link between Hsp90 and the PKA signaling cascade. Sgt1 also mediates tolerance and resistance to the two most widely deployed classes of antifungal drugs, azoles and echinocandins. Depletion of Sgt1 abrogates basal tolerance and acquired resistance to azoles, which target the cell membrane. Depletion of Sgt1 also abrogates tolerance and resistance to echinocandins, which target the cell wall, and renders echinocandins fungicidal. Though Sgt1 and Hsp90 have a conserved impact on drug resistance, the underlying mechanisms are distinct. Depletion of Hsp90 destabilizes the client protein calcineurin, thereby blocking crucial responses to drug-induced stress; in contrast, depletion of Sgt1 does not destabilize calcineurin, but blocks calcineurin activation in response to drug-induced stress. Sgt1 influences not only morphogenesis and drug resistance, but also virulence, as genetic depletion of C. albicans Sgt1 leads to reduced kidney fungal burden in a murine model of systemic infection. Thus, our characterization of the first Hsp90 co-chaperone in a fungal pathogen establishes C. albicans Sgt1 as a global regulator of morphogenesis and drug resistance, providing a new target for treatment of life-threatening fungal infections.
Comparision of biofilm production and multiple drug resistance in clinical isolates of Acinetobacter baumanii from a tertiary care hospital in South India
M. Dheepa,Vinitha L Rashme,B. Appalaraju
International Journal of Pharmacy and Biomedical Sciences , 2011,
Abstract: The present work is aimed at to determine biofilm formation in clinical isolates of Acinetobacter baumannii and to determine the antibiotic susceptibility pattern of seventeen different antibiotics and to correlate between biofilm production and multidrug resistance. A total of 50 isolates were screened for biofilm production by both qualitative and quantitative method in Acinetobacter baumannii isolates. Biofilm production is demonstrated with standard tube test method, in which bacterial film lining a culture tube is stained with a cationic dye and visually scaled. In the second microtitre plate method, the optical density of the stained bacterial film is determined spectrophotometrically. In biofilm production, both qualitative (tube method) and quantitative (microtitre plate) method showed 30 isolates (60%) as biofilm producers. Resistance to antibiotics such as ceftazidime, cefepime and pipercillin was comparatively higher among biofilm producers than non-biofilm producers .Our investigations showed a simultaneous emergence of resistance to many antimicrobial agents available and represent a severe threat in the treatment of hospitalized patients. This study demonstrates a high propensity among the clinical isolates of A. baumannii to form biofilm and a significant association of biofilm with multiple drug resistance.
A Systems Biology Approach to Drug Targets in Pseudomonas aeruginosa Biofilm  [PDF]
Gunnar Sigurdsson, Ronan M. T. Fleming, Almut Heinken, Ines Thiele
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034337
Abstract: Antibiotic resistance is an increasing problem in the health care system and we are in a constant race with evolving bacteria. Biofilm-associated growth is thought to play a key role in bacterial adaptability and antibiotic resistance. We employed a systems biology approach to identify candidate drug targets for biofilm-associated bacteria by imitating specific microenvironments found in microbial communities associated with biofilm formation. A previously reconstructed metabolic model of Pseudomonas aeruginosa (PA) was used to study the effect of gene deletion on bacterial growth in planktonic and biofilm-like environmental conditions. A set of 26 genes essential in both conditions was identified. Moreover, these genes have no homology with any human gene. While none of these genes were essential in only one of the conditions, we found condition-dependent genes, which could be used to slow growth specifically in biofilm-associated PA. Furthermore, we performed a double gene deletion study and obtained 17 combinations consisting of 21 different genes, which were conditionally essential. While most of the difference in double essential gene sets could be explained by different medium composition found in biofilm-like and planktonic conditions, we observed a clear effect of changes in oxygen availability on the growth performance. Eight gene pairs were found to be synthetic lethal in oxygen-limited conditions. These gene sets may serve as novel metabolic drug targets to combat particularly biofilm-associated PA. Taken together, this study demonstrates that metabolic modeling of human pathogens can be used to identify oxygen-sensitive drug targets and thus, that this systems biology approach represents a powerful tool to identify novel candidate antibiotic targets.
Development of a High-Throughput Candida albicans Biofilm Chip  [PDF]
Anand Srinivasan,Priya Uppuluri,Jose Lopez-Ribot,Anand K. Ramasubramanian
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019036
Abstract: We have developed a high-density microarray platform consisting of nano-biofilms of Candida albicans. A robotic microarrayer was used to print yeast cells of C. albicans encapsulated in a collagen matrix at a volume as low as 50 nL onto surface-modified microscope slides. Upon incubation, the cells grow into fully formed “nano-biofilms”. The morphological and architectural complexity of these biofilms were evaluated by scanning electron and confocal scanning laser microscopy. The extent of biofilm formation was determined using a microarray scanner from changes in fluorescence intensities due to FUN 1 metabolic processing. This staining technique was also adapted for antifungal susceptibility testing, which demonstrated that, similar to regular biofilms, cells within the on-chip biofilms displayed elevated levels of resistance against antifungal agents (fluconazole and amphotericin B). Thus, results from structural analyses and antifungal susceptibility testing indicated that despite miniaturization, these biofilms display the typical phenotypic properties associated with the biofilm mode of growth. In its final format, the C. albicans biofilm chip (CaBChip) is composed of 768 equivalent and spatially distinct nano-biofilms on a single slide; multiple chips can be printed and processed simultaneously. Compared to current methods for the formation of microbial biofilms, namely the 96-well microtiter plate model, this fungal biofilm chip has advantages in terms of miniaturization and automation, which combine to cut reagent use and analysis time, minimize labor intensive steps, and dramatically reduce assay costs. Such a chip should accelerate the antifungal drug discovery process by enabling rapid, convenient and inexpensive screening of hundreds-to-thousands of compounds simultaneously.
Correlation between biofilm production and multiple drug resistance in imipenem resistant clinical isolates of Acinetobacter baumannii  [cached]
Rao R,Karthika R,Singh S,Shashikala P
Indian Journal of Medical Microbiology , 2008,
Abstract: Purpose: To study the qualitative and quantitative methods for the investigation of biofilm formation and to examine the correlation between biofilm and antibiotic resistance among the clinical isolates of Acinetobacter baumannii . We also verified the association between biofilm and presence of extended spectrum β-lactamases, particularly, bla PER-1 . Methods: A total of 55 isolates were subjected to susceptibility testing by disc diffusion method for 13 clinically relevant antibiotics. Screening for biofilm production was done by both qualitative and quantitative methods through tube and microtitre plate assay respectively. The presence of bla PER-1 was checked by PCR. Results: A. baumannii isolates showed very high resistance (>75%) to imipenem, cephotaxime, amikacin and ciprofloxacin. Only cefoperazone, netillin and norfloxacin were found to be effective agents. Results of microtitre and tube methods were concordant with 34 isolates (62%) showing biofilm formation. Resistance to four antibiotics such as amikacin (82% vs. 17.6%, P < 0.001), cephotaxime (88% vs. 11%, P P < 0.001), ciprofloxacin (70% vs. 29%, P =0.005) and aztreonam (38% vs. 11%, P =0.039) was comparatively higher among biofilm producers than non-biofilm producers. Microtitre assay additionally detected 14 weakly adherent isolates. Only 11 isolates had bla PER-1 gene and among these two were strong biofilm producers, while remaining were weakly adherent isolates. Conclusion: Microtitre plate method was found to be a more sensitive method for biofilm detection. This study demonstrates a high propensity among the clinical isolates of A. baumannii to form biofilm and a significant association of biofilms with multiple drug resistance. Presence of bla PER-1 appears to be more critical for cell adherence than for biofilm formation.
Biohybrid Nanostructured Iron Oxide Nanoparticles and Satureja hortensis to Prevent Fungal Biofilm Development  [PDF]
Ion Anghel,Alexandru Mihai Grumezescu,Alina Maria Holban,Anton Ficai,Alina Georgiana Anghel,Mariana Carmen Chifiriuc
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140918110
Abstract: Cutaneous wounds are often superinfected during the healing process and this leads to prolonged convalescence and discomfort. Usage of suitable wound dressings is very important for an appropriate wound care leading to a correct healing. The aim of this study was to demonstrate the influence of a nano-coated wound dressing (WD) on Candida albicans colonization rate and biofilm formation. The modified WD was achieved by submerging the dressing pieces into a nanofluid composed of functionalized magnetite nanoparticles and Satureja hortensis (SO) essential oil (EO). Chemical composition of the EO was established by GC-MS. The fabricated nanostructure was characterized by X-ray Diffraction (XRD), Transmission Electron Microscopy (TEM), Differential Thermal Analysis (DTA) and Fourier Transform-Infrared Spectroscopy (FT-IR). The analysis of the colonized surfaces using (Scanning Electron Microscopy) SEM revealed that C. albicans adherence and subsequent biofilm development are strongly inhibited on the surface of wound dressing fibers coated with the obtained nanofluid, comparing with regular uncoated materials. The results were also confirmed by the assay of the viable fungal cells embedded in the biofilm. Our data demonstrate that the obtained phytonanocoating improve the resistance of wound dressing surface to C. albicans colonization, which is often an etiological cause of local infections, impairing the appropriate wound healing.
Hemolysins of Staphylococcus aureus—An Update on Their Biology, Role in Pathogenesis and as Targets for Anti-Virulence Therapy  [PDF]
Sireesha Divyakolu, Rosy Chikkala, Kamaraju Suguna Ratnakar, Venkataraman Sritharan
Advances in Infectious Diseases (AID) , 2019, DOI: 10.4236/aid.2019.92007
Abstract: Staphylococcus aureus is a dangerous gram positive bacterial pathogen which, not only evades the host’s immune system but also can destroy the leucocytes especially neutrophils. It has an embodiment of virulence factors most of which are secreted. Staphylococcus aureus secretes a number of toxins which cause tissue damage and facilitate spreading and nutrients uptake. Among the toxins, hemolysins α, β, γ, δ and Panton Valentine Leukocidin (PVL) are unique that they drill pores in the membrane, leading to the efflux of vital molecules and metabolites. Hemolysins also help in the scavenging of iron, although many of them also have leucolytic properties. α-hemolysin, also known as α-toxin, is the most prominent cytotoxin which damages a wide range of host cells including epithelial cells, endothelial cells, erythrocytes, monocytes, keratinocytes and it damages cell membrane and induces apoptosis. β-Hemolysin significantly affects human immune cell function. It has Mg2+ dependent sphingomyelinase activity and degrades sphingomyelin of plasma membrane into phosphorylcholine and ceramides. The bi-component leukocidins, which include γ-hemolysin and PVL, attack human phagocytic cells and greatly contribute to immune evasion. Delta toxin is a low molecular weight exotoxin with a broad cytolytic activity. Virulence determinants, quorum sensing and biofilm synthesis provide some attractive targets for design and development of a new group of antimicrobial compounds. This review provides an update on the structure, biological functions of hemolysins and their role in quorum sensing/biofilm synthesis (if any) and as effective therapeutic targets for anti-virulence drug development. We have tried to bring together information available on various aspects of hemolysins and highlighted their distribution among all species of Staphylococcus and other bacteria. We have updated the status of development of candidate drugs targeting the hemolysins for anti-virulence therapy as it offers an additional strategy to reduce the severity of infection and which would, through quorum quenching, delay the development biofilms leading to drug resistance.
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