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Biomedical subjects

A D Ferguson

Publications and source records attributed to A D Ferguson.

At least 19 recordsLinked to original sources
PubMed2002

Cross-reactivity patterns to budesonide.

Allergic contact dermatitis from topical corticosteroids is not uncommon. Budesonide has been included in the European standard series as a marker for corticosteroid allergy, though little is known of its cross-reactivity with other corticosteroids. Twelve patients previously positive to budesonide on patch testing were given further patch and intradermal tests to a range of corticosteroids. Six patients previously negative to budesonide on patch testing were used as a control group. Budesonide cross-reacts with hydrocortisone-21-sodium phosphate and triamcinolone acetonide. Patients positive to budesonide should therefore avoid hydrocortisone and triamcinolone acetonide. Patch testing, unfortunately, is an inaccurate method of determining cross-reactivity patterns among corticosteroids.

Administration, Topical↗
PubMed2002

Bipartite gating in the outer membrane protein FecA.

The recent structure determination of FecA, with and without ligand, shows the existence of two gates. These are the extracellular loops closing over the binding site and the plug located inside the barrel. It indicates a process which is described as bipartite gating and allows for a rational distinction between the binding event and the transport process.

Bacterial Outer Membrane Proteins↗
PubMed2002

Size matters.

Explore the source record for details and available documents.

Dermatology↗
PubMed2001

Active transport of an antibiotic rifamycin derivative by the outer-membrane protein FhuA.

BACKGROUND: FhuA, an integral membrane protein of Escherichia coli, actively transports ferrichrome and the structurally related antibiotic albomycin across the outer membrane. The transport is coupled to the proton motive force, which energizes FhuA through the inner-membrane protein TonB. FhuA also transports the semisynthetic rifamycin derivative CGP 4832, although the chemical structure of this antibiotic differs markedly from that of ferric hydroxamates. RESULTS: X-ray crystallography revealed that rifamycin CGP 4832 occupies the same ligand binding site as ferrichrome and albomycin, thus demonstrating a surprising lack of selectivity. However, the binding of rifamycin CGP 4832 is deviant from the complexes of FhuA with hydroxamate-type ligands in that it does not result in the unwinding of the switch helix but only in its destabilization, as reflected by increased B factors. Unwinding of the switch helix is proposed to be required for efficient binding of TonB to FhuA and for coupling the proton motive force of the cytoplasmic membrane with energy-dependent ligand transport. The transport data from cells expressing mutant FhuA proteins indicated conserved structural and mechanistic requirements for the transport of both types of compounds. CONCLUSIONS: We conclude that the binding of rifamycin CGP 4832 destabilizes the switch helix and promotes the formation of a transport-competent FhuA-TonB complex, albeit with lower efficiency than ferrichrome. Active transport of this rifamycin derivative explains the 200-fold increase in potency as compared to rifamycin, which is not a FhuA-specific ligand and permeates across the cell envelope by passive diffusion only.

Allosteric Site↗
PubMed2000

A conserved structural motif for lipopolysaccharide recognition by procaryotic and eucaryotic proteins.

BACKGROUND: Lipopolysaccharide (LPS), a lipoglycan from the outer membrane of Gram-negative bacteria, is an immunomodulatory molecule that stimulates the innate immune response. High levels of LPS cause excessive release of inflammatory mediators and are responsible for the septic shock syndrome. The interaction of LPS with its cognate binding proteins has not, as yet, been structurally elucidated. RESULTS: The X-ray crystallographic structure of LPS in complex with the integral outer membrane protein FhuA from Escherichia coli K-12 is reported. It is in accord with data obtained using mass spectroscopy and nuclear magnetic resonance. Most of the important hydrogen-bonding or electrostatic interactions with LPS are provided by eight positively charged residues of FhuA. Residues in a similar three-dimensional arrangement were searched for in all structurally known proteins using a fast template-matching algorithm, and a subset of four residues was identified that is common to known LPS-binding proteins. CONCLUSIONS: These four residues, three of which form specific interactions with lipid A, appear to provide the structural basis of pattern recognition in the innate immune response. Their arrangement can serve to identify LPS-binding sites on proteins known to interact with LPS, and could serve as a template for molecular modeling of a LPS scavenger designed to reduce the septic shock syndrome.

Acute-Phase Proteins↗
PubMed2000

Crystal structure of the antibiotic albomycin in complex with the outer membrane transporter FhuA.

One alternative method for drug delivery involves the use of siderophore-antibiotic conjugates. These compounds represent a specific means by which potent antimicrobial agents, covalently linked to iron-chelating siderophores, can be actively transported across the outer membrane of gram-negative bacteria. These "Trojan Horse" antibiotics may prove useful as an efficient means to combat multi-drug-resistant bacterial infections. Here we present the crystallographic structures of the natural siderophore-antibiotic conjugate albomycin and the siderophore phenylferricrocin, in complex with the active outer membrane transporter FhuA from Escherichia coli. To our knowledge, this represents the first structure of an antibiotic bound to its cognate transporter. Albomycins are broad-host range antibiotics that consist of a hydroxamate-type iron-chelating siderophore, and an antibiotically active, thioribosyl pyrimidine moiety. As observed with other hydroxamate-type siderophores, the three-dimensional structure of albomycin reveals an identical coordination geometry surrounding the ferric iron atom. Unexpectedly, this antibiotic assumes two conformational isomers in the binding site of FhuA, an extended and a compact form. The structural information derived from this study provides novel insights into the diverse array of antibiotic moieties that can be linked to the distal portion of iron-chelating siderophores and offers a structural platform for the rational design of hydroxamate-type siderophore-antibiotic conjugates.

Anti-Bacterial Agents↗
PubMed1999

Epidemiological features of drug resistant tuberculosis in Harare, 1994 to 1996.

OBJECTIVES: To characterise the prevalence, clinical and radiological features of drug resistant tuberculosis in selected patients with pulmonary tuberculosis in Harare between 1994 and 1996. DESIGN: A retrospective review of medical and microbiological records. SETTING: Beatrice Road Infectious Diseases Hospital, Harare, Zimbabwe. SUBJECTS: 381 smear-positive tuberculosis patients who had samples submitted to the National Tuberculosis Reference Laboratory for culture and susceptibility testing. MAIN OUTCOME MEASURES: Prevalence of resistance of isolated cultures of Mycobacterium tuberculosis to anti-tuberculosis drugs; clinical, radiological and microbiological response to treatment with recommended anti-tuberculosis regimens. RESULTS: Resistance to one or more drugs was detected in 16 isolates (16/165, 9.7%), single drug resistance in five (3.0%) and resistance to two or more drugs in 11 (6.7%). There were no distinctive clinical or radiological features of drug-resistant tuberculosis, although a higher percent of drug resistant cases had evidence of pleural disease (25% vs 2.5%, p = 0.005). Neither past history of tuberculosis or known or suspected HIV infection was associated with the presence of drug resistance. CONCLUSIONS: In spite of the resurgence of tuberculosis and the high prevalence of HIV infection in Zimbabwe, the rates of drug resistance have remained relatively low, even among a selected population at high risk of resistance. A significant proportion of cases of drug-resistant tuberculosis appear to be due to new transmission of drug resistant strains, which reinforces the importance of maintaining a surveillance system for the monitoring of drug susceptibility. Ongoing prospective studies should provide more reliable estimates of the prevalence and determinants of drug resistance in Zimbabwe.

Adolescent↗
PubMed1998

Siderophore-mediated iron transport: crystal structure of FhuA with bound lipopolysaccharide.

FhuA, the receptor for ferrichrome-iron in Escherichia coli, is a member of a family of integral outer membrane proteins, which, together with the energy-transducing protein TonB, mediate the active transport of ferric siderophores across the outer membrane of Gram-negative bacteria. The three-dimensional structure of FhuA is presented here in two conformations: with and without ferrichrome-iron at resolutions of 2.7 and 2.5 angstroms, respectively. FhuA is a beta barrel composed of 22 antiparallel beta strands. In contrast to the typical trimeric arrangement found in porins, FhuA is monomeric. Located within the beta barrel is a structurally distinct domain, the "cork," which mainly consists of a four-stranded beta sheet and four short alpha helices. A single lipopolysaccharide molecule is noncovalently associated with the membrane-embedded region of the protein. Upon binding of ferrichrome-iron, conformational changes are transduced to the periplasmic pocket of FhuA, signaling the ligand-loaded status of the receptor. Sequence homologies and mutagenesis data are used to propose a structural mechanism for TonB-dependent siderophore-mediated transport across the outer membrane.

Bacterial Outer Membrane Proteins↗
PubMed1998

An internal affinity-tag for purification and crystallization of the siderophore receptor FhuA, integral outer membrane protein from Escherichia coli K-12.

FhuA (Mr 78,992, 714 amino acids), siderophore receptor for ferrichrome-iron in the outer membrane of Escherichia coli, was affinity tagged, rapidly purified, and crystallized. To obtain FhuA in quantities sufficient for crystallization, a hexahistidine tag was genetically inserted into the fhuA gene after amino acid 405, which resides in a known surface-exposed loop. Recombinant FhuA405.H6 was overexpressed in an E. coli strain that is devoid of several major porins and using metal-chelate chromatography was purified in large amounts to homogeneity. FhuA crystals were grown using the hanging drop vapor diffusion technique and were suitable for X-ray diffraction analysis. On a rotating anode X-ray source, diffraction was observed to 3.0 A resolution. The crystals belong to space group P6(1) or P6(5) with unit cell dimensions of a=b=174 A, c=88 A (alpha=beta=90 degrees, gamma=120 degrees).

Bacterial Outer Membrane Proteins↗
PubMed1996

The clinical course and management of thoracic empyema.

We report a prospective multi-centre study of the clinical course and hospital management of thoracic empyema in 119 patients (mean age 54.8). The commonest presenting symptom was malaise (75%), 55% were febrile; 31% were previously well with no predisposing condition. Initial treatments were antibiotics alone (5), needle aspirations (46), intercostal tube drainage (61), rib resection (3) and decortication (4). Overall, intercostal drainage was used in 77 patients (16 failed aspirations), surgical rib resection in 24 (1 failed aspirations, 20 failed drainage), and surgical decortication in 28 (6 failed aspirations, 17 failed drainage). Only 4 patients received intrapleural fibrinolytic agents. Aspiration and drainage were likely to fail if the empyema was > 40% of the hemithorax. Median time from treatment start to discharge was: aspirations, 26 days; drainage, 23 days; resection 11 days; decortication, 12 days. Overall 21 patients died (12 with empyema as the major cause); two had been surgically treated. Mortality correlated with age, diabetes, heart failure, and low serum albumin at admission. Infecting organisms, identified in 109 patients (92%) included anaerobes (37), Str. melleri (36), and Str. pneumoniae (28). Six months after discharge, all but six survivors had regained their previous health.

Adolescent↗
PubMed1989

Chronic obstructive airways disease following treated pulmonary tuberculosis.

Seventy-one subjects who had previously been treated for tuberculosis up to 16 years before underwent pulmonary function assessment. Evidence of airways obstruction was found in 48 (68%). There was an inverse relationship between the extent of the disease on the original chest radiograph and the forced expired volume in one second (FEV1). A similar inverse relationship between the amount of sputum produced and the FEV1 and the original chest radiograph was also found. Treated pulmonary tuberculosis is a cause of significant chronic obstructive airways disease.

Adolescent↗
PubMed1981

Fibre-optic bronchoscopy. Experience at Groote Schuur Hospital.

The 4-year experience with flexible fibre-optic bronchoscopy at Groote Schuur Hospital is presented. A total of 809 patients were bronchoscoped, follow-up data on 705 being available. The procedure was performed for a wide variety of indications, suspected malignant disease and tuberculosis being the two most common. The diagnostic rate in these conditions was 74% and 71% respectively. Other indications included the evaluation of diffuse pulmonary lesions, shadows on the chest radiographs in immunocompromised patients, use in the intensive care unit, investigation of haemoptysis with a normal chest radiograph, inspection of the airway, bronchography and clearance of secretions.

Biopsy↗
PubMed1981

Surgical treatment of bullous lung disease.

Clear guidelines for the selection of patients with large pulmonary bullae and severely impaired lung function for surgery remain to be defined. Twenty-one such patients operated on between 1971 and 1977 are reviewed in an attempt to shed some light on this difficult problem. Four of six patients with preoperative hypercapnia survived and were improved by surgery. There was no mortality among the remaining 15 patients of whom 14 were improved symptomatically by surgery (with improvement in FEV1 and vital capacity in 9). Preoperative bronchograms were used to help identify patients suitable for surgery. The presence of bronchiectasis was predictive of postoperative complications. Better results were obtained in those patients in whom plication of bullectomy could be performed than in those requiring lobectomy.

Adolescent↗