Science Progress (2002), 85 (1)
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Science Progress (2002), 85 (1), 1–11
Introduction: Microbial disease:
recent studies show that novel
extracellular components can
enhance microbial resistance to
lethal host chemicals and
increase virulence
ROBIN J. ROWBURY
This volume, in the main, covers a range of topics related to infectious
disease caused by organisms which are, at present, or permanently,
in the news. Many of these organisms are of substantial public concern,
because of major health problems involving them. The article
by Basset et al.1, for example, reviews Helicobacter; who would
have believed, 20 years ago, that gastric and duodenal ulcer and
possibly gastric cancer, would be linked to the presence of a novel
helical bacterium, in the stomach, and no doubt, even fewer would
have anticipated the possible involvement of this organism in other
diseases. The demonstrated involvement of Helicobacter has
enabled clinicians, in some cases, to successfully use antimicrobials
to alleviate these conditions. Basset and Holton review factors that
influence the occurrence of inflammatory bowel disease, emphasising
particularly immunological and bacteriological aspects2; again,
strikingly, there is some evidence for the involvement of Helicobacter
spp in such disorders, although the evidence is much less substantial.
Hopefully, further studies will enable these painful and often intransigent
disorders to be much more readily alleviated.
Science Progress (2002), 85 (1), 13–31
Helicobacter: a paradigm shift in
peptic ulcer disease and more?
CHRISTELLE BASSET, JOHN HOLTON AND DINO VAIRA
There are many diseases where the cause is unknown and this makes a
specific treatment difficult. In many cases all that can be achieved is amelioration
of the illness. Peptic ulcer disease was one such condition no
more that 20 years ago. The management was drastic – either an operation
or life-long medication in order to reduce the acid secreted by the stomach.
However, the cause of this condition was discovered in 1983. Although initially
sceptical, the medical fraternity now almost universally endorse
Helicobacter pylori as the cause of the majority of stomach ulcers. Peptic
ulcers can now be cured by antibiotics. This is a major shift in medical
practice. Continued investigations on Helicobacter pylori are bringing to
light other possible associations with disease as well as delineating plausible
biological mechanisms for disease pathogenesis.
Science Progress (2002), 85 (1), 33–56
Inflammatory bowel disease:
is the intestine a Trojan horse?
CHRISTELLE BASSET AND JOHN HOLTON
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory
condition of the intestines that is clinically heterogenous. The cause(s) of
IBD are currently unknown but the mechanisms of injury are immunological.
Increasingly there is an emphasis on the study of the complex interactions
at the interface of self and non-self- the gastrointestinal epithelial
surface- in relationship to the pathogenesis of disease. There is mounting
evidence that a lack of tolerance to the normal commensal flora of the intestine
may underly the disease pathogenesis. Several genetic loci that are
markers of disease susceptibility have been identified. These loci map to
areas of the genome that are concerned with antigen presentation or
cytokine secretion and suggest a genetic heterogeneity that underlies the
clinical differences. Overall a picture is emerging of defects in epithelial
barrier function and, or immunoregulation leading to immune responses
that are triggered or exaggerated by the antigenic components of the normal
flora.
Science Progress (2002), 85 (1), 57–72
Methicillin resistance in
Staphylococcus aureus:
mechanisms and modulation
PAUL D. STAPLETON AND PETER W. TAYLOR
Staphylococcus aureus is a major pathogen both within hospitals and in the
community. Methicillin, a _-lactam antibiotic, acts by inhibiting penicillinbinding
proteins (PBPs) that are involved in the synthesis of peptidoglycan,
an essential mesh-like polymer that surrounds the cell. S. aureus can
become resistant to methicillin and other _-lactam antibiotics through the
expression of a foreign PBP, PBP2a, that is resistant to the action of methicillin
but which can perform the functions of the host PBPs. Methicillinresistant
S. aureus isolates are often resistant to other classes of antibiotics
(through different mechanisms) making treatment options limited, and this
has led to the search for new compounds active against these strains. An
understanding of the mechanism of methicillin resistance has led to the discovery
of accessory factors that influence the level and nature of methicllin
resistance. Accessory factors, such as Fem factors, provide possible new
targets, while compounds that modulate methicillin resistance such as epicatechin
gallate, derived from green tea, and corilagin, provide possible
lead compounds for development of inhibitors.
Science Progress (2002), 85 (1), 73–88
Prospects for generating new
antibiotics
ALASTAIR C.W. WAUGH AND PAUL F. LONG
A plethora of human pathogens are now resistant to all clinically significant
antibiotics causing a crisis, in the treatment and management of infectious
diseases, but also presenting a clear danger to future public health. If
drug resistance is going to be tackled successfully, new antibiotics must be
continually developed to counteract the processes of evolution and natural
selection in these populations of pathogens. Despite the introduction of
powerful new technologies such as high throughput screening platforms
and combinatorial chemistry, natural products still offer structural diversity
worthy of screening for biological activity. Functional genomics can
revolutionise rational drug design providing new targets for antimicrobial
drug discovery. The clusters of genes, encoding enzymes that form biosynthetic
pathways leading to the synthesis of many natural products
including polyketides and non-ribosomal peptides, are amenable to modern
genetic engineering. Repositioning, deleting and replacing genes in these
biosynthetic clusters has resulted in the synthesis of many ‘un-natural’
natural products. This review examines the engineering of proteins
involved in chain initiation on polyketide synthases culminating in the production
at high yield of a biologically active erythromycin derivative.
Science Progress (2002), 85 (1), 89–111
Resistance to antifolates in
Plasmodium falciparum, the
causative agent of tropical
malaria
DAVID C. WARHURST
Every year there are 270 million clinical attacks of malaria and 2 million
deaths, caused by the protozoan Plasmodium falciparum. Most of these
cases occur in Africa. Chloroquine-resistance has led to reliance on antimalarial
antifolates, in particular the synergistic combination sulfadoxine/
pyrimethamine (S/P) which targets enzymatic synthesis of folate co-factors
through dihydropteroate synthase (DHPS) and dihydrofolate reductase
(DHFR). Resistance to S/P is now increasing and replacement antimalarials
are needed. Crystal structures are not yet available for these key enzymes
in the folate pathway. This review focuses on the activity of drugs on DHFR
in malaria parasites, attempts to interpret differences in activity of
pyrimethamine and its related drugs, and to clarify how residue changes
due to point mutations determine the development of resistance.
In homology-modelled P. falciparum DHFR (PfDHFR) , the typical
structure of four _-helices, 8-stranded _-sheet, four Loops and eight Turns
is clearly seen. Long polar sequences specific for Plasmodium are inserted
in Turns 1 and 2. Structures immediately concerned in drug binding are
b-A, L1, a-B, a-C, T-3, b-E, a-F, and b-F. The roles of several mutations
associated with resistance are discussed. In view of sequence differences in
turn 3 in PfDHFR and in the human enzyme, and the marked interaction
with residues of T3 of the experimental flexible antifolate WR99210 effective
in pyrimethamine and cycloguanil resistance, further drug development
in this area is indicated.