4 research outputs found
Medicinal plants used in the treatment of human immunodeficiency virus
Since the beginning of the epidemic, human immunodeficiency virus (HIV) has infected around 70 million people worldwide, most of whom reside is sub-Saharan Africa. There have been very promising developments in the treatment of HIV with anti-retroviral drug cocktails. However, drug resistance to anti-HIV drugs is emerging, and many people infected with HIV have adverse reactions or do not have ready access to currently available HIV chemotherapies. Thus, there is a need to discover new anti-HIV agents to supplement our current arsenal of anti-HIV drugs and to provide therapeutic options for populations with limited resources or access to currently efficacious chemotherapies. Plant-derived natural products continue to serve as a reservoir for the discovery of new medicines, including anti-HIV agents. This review presents a survey of plants that have shown anti-HIV activity, both in vitro and in vivo
Studies on natural products: resistance modifying agents, antibacterials and structure elucidation
This thesis describes research starting in 1999 on three areas of natural product
science, namely bacterial resistance modifying agents, antibacterials and structure
elucidation of natural products.
Plants produce an array of structurally-complex and diverse chemical scaffolds and
whilst there is an expanding volume of published literature on structure elucidation,
there remains a need to understand why these compounds are produced and how
they function in terms of biological activity. That can only be properly realised by a
full and determined attempt at structure elucidation. This is an important concept as
molecular structure describes and precedes function. The chirality and functional
group chemistry of natural products defines the way in which a compound
specifically binds to a receptor, protein or drug target.
My independent research career started with studies on the ability of plant extracts
and phytochemicals to modulate the activity of antibiotics that are substrates for
bacterial multidrug efflux. These investigations are described in the first section,
âNatural Product Resistance Modifying Agentsâ. Studies were, in the first instance,
simple assays to look at potentiation and synergy of extracts and pure
phytochemicals to potentiate the activity of antibiotics against resistant bacteria. This
research evolved to study efflux inhibition, where we learnt much from the
collaborations with Professors Piddock (Birmingham), Kaatz (Wayne State) and
Bhakta (Birkbeck). Latterly, we were inspired by the highly imaginative and creative
work of Dr Paul Stapleton (UCL), to study the plasmid transfer inhibitory effects of
natural products; the rationale being that plasmids carry antibiotic-resistance genes
and virulence factors. Inhibition of transfer could result in a reduction in the spread of
antibiotic resistance and a reduction in pathogenicity.
The second section of this thesis describes antibacterial natural products that were
evaluated against clinically-relevant species of bacteria, in the main Gram-positive
organisms such as Staphylococcus aureus and its methicillin- (MRSA) and
multidrug-resistant variants and Mycobacterium tuberculosis, the causative agent of
tuberculosis, which still continues to affect millions of people globally and for which
antibiotic resistance is considerable.
The papers described in this section detail the extraction of the plant and the
bioassay-guided isolation of the active compounds, which were then subjected to
structure elucidation, using in the majority of cases, Nuclear Magnetic Resonance
(NMR) spectroscopy, High-Resolution Mass Spectrometry, and Infrared and
Ultraviolet-Visible Spectroscopy. Natural products from the acylphloroglucinol,
terpenoid, polyacetylene, alkaloid and sulphide classes are well represented in these
publications with some of these antibacterial natural products displaying minimum
inhibitory concentrations (MIC) values of less than 1 mg/L against MRSA and
Mycobacterium tuberculosis strains. These activity levels approach those of existing
clinically used antibiotics and this highlights the value of plant natural products as a
resource for antibacterial templates.
Mechanistic studies have also been conducted on selected compounds, for example
the natural products from Hypericum acmosepalum were found to inhibit ATP-
dependent MurE ligase, a key enzyme involved in bacterial cell wall biosynthesis.
Other examples included the main component of cinnamon (Cinnamomum
zeylanicum), an ancient medicinal material cited in the Bible in Exodus, which has
been used in antiquity as an anti-infective substance. The main compound from this
medicinal material is trans-cinnamaldehyde, a simple phenylpropanoid which has
been shown to inhibit Acetyl-CoA Carboxylase, a pivotal enzyme that catalyses the
first committed step in fatty acid biosynthesis in all animals, plants and bacteria. In
collaboration with the marine natural product chemist Professor Vassilios Roussis,
we have also been able to characterise the antibacterial activities of marine plants,
particularly compounds of the diterpene class that display promising levels of
antibacterial activity against MRSA and S. aureus strains. Work on the antibacterial
properties of Cannabis sativa showed that some of the main cannabinoids display
excellent potency towards drug-resistant variants of S. aureus and support the
ancient medicinal usage of Cannabis as an anti-infective and wound healing
preparation. The acylphloroglucinol class of plant natural products are also
noteworthy, particularly from Hypericum and Mediterranean medicinal plant species
such as Myrtle (Myrtus communis), again with MIC values reaching 1 mg/L against
pathogenic bacteria. We synthesised some of these acylphloroglucinols and made
analogues and not surprisingly, were unable to improve the activity as nature really
is the best chemist of all.
The final section describes early and continuing research into the isolation and
structure elucidation of natural products from plants and microbes. The rationale for
this research is manifold: training for isolation to understand the medicinal use of a
plant or microbe, chemotaxonomic investigations, the ecological relevance of
phytochemicals in plants that are halophytic and xerophytic and in some cases just
plain academic curiosity. These studies use classical phytochemical techniques to
isolate and determine the structures of the species of investigation and where
possible, absolute stereochemistry is undertaken. It should be noted however that
isolation can be exceptionally challenging and frustrating. This can be due to the
paucity of biomass, low concentrations of compounds, complexity of the resulting
natural product mixtures and finally a lack of chemical stability of the products. All of
these issues need to be faced before structure determination can even be
attempted. A word of caution is therefore needed to the young natural product
chemist embarking on their first isolation project. However, words of encouragement
are also needed: the isolation of new, chemically complex and exquisitely biologically
active molecules is a beautiful endeavour and exceptionally rewarding on many
levels.This thesis describes research starting in 1999 on three areas of natural product
science, namely bacterial resistance modifying agents, antibacterials and structure
elucidation of natural products.
Plants produce an array of structurally-complex and diverse chemical scaffolds and
whilst there is an expanding volume of published literature on structure elucidation,
there remains a need to understand why these compounds are produced and how
they function in terms of biological activity. That can only be properly realised by a
full and determined attempt at structure elucidation. This is an important concept as
molecular structure describes and precedes function. The chirality and functional
group chemistry of natural products defines the way in which a compound
specifically binds to a receptor, protein or drug target.
My independent research career started with studies on the ability of plant extracts
and phytochemicals to modulate the activity of antibiotics that are substrates for
bacterial multidrug efflux. These investigations are described in the first section,
âNatural Product Resistance Modifying Agentsâ. Studies were, in the first instance,
simple assays to look at potentiation and synergy of extracts and pure
phytochemicals to potentiate the activity of antibiotics against resistant bacteria. This
research evolved to study efflux inhibition, where we learnt much from the
collaborations with Professors Piddock (Birmingham), Kaatz (Wayne State) and
Bhakta (Birkbeck). Latterly, we were inspired by the highly imaginative and creative
work of Dr Paul Stapleton (UCL), to study the plasmid transfer inhibitory effects of
natural products; the rationale being that plasmids carry antibiotic-resistance genes
and virulence factors. Inhibition of transfer could result in a reduction in the spread of
antibiotic resistance and a reduction in pathogenicity.
The second section of this thesis describes antibacterial natural products that were
evaluated against clinically-relevant species of bacteria, in the main Gram-positive
organisms such as Staphylococcus aureus and its methicillin- (MRSA) and
multidrug-resistant variants and Mycobacterium tuberculosis, the causative agent of
tuberculosis, which still continues to affect millions of people globally and for which
antibiotic resistance is considerable.
The papers described in this section detail the extraction of the plant and the
bioassay-guided isolation of the active compounds, which were then subjected to
structure elucidation, using in the majority of cases, Nuclear Magnetic Resonance
(NMR) spectroscopy, High-Resolution Mass Spectrometry, and Infrared and
Ultraviolet-Visible Spectroscopy. Natural products from the acylphloroglucinol,
terpenoid, polyacetylene, alkaloid and sulphide classes are well represented in these
publications with some of these antibacterial natural products displaying minimum
inhibitory concentrations (MIC) values of less than 1 mg/L against MRSA and
Mycobacterium tuberculosis strains. These activity levels approach those of existing
clinically used antibiotics and this highlights the value of plant natural products as a
resource for antibacterial templates.
Mechanistic studies have also been conducted on selected compounds, for example
the natural products from Hypericum acmosepalum were found to inhibit ATP-
dependent MurE ligase, a key enzyme involved in bacterial cell wall biosynthesis.
Other examples included the main component of cinnamon (Cinnamomum
zeylanicum), an ancient medicinal material cited in the Bible in Exodus, which has
been used in antiquity as an anti-infective substance. The main compound from this
medicinal material is trans-cinnamaldehyde, a simple phenylpropanoid which has
been shown to inhibit Acetyl-CoA Carboxylase, a pivotal enzyme that catalyses the
first committed step in fatty acid biosynthesis in all animals, plants and bacteria. In
collaboration with the marine natural product chemist Professor Vassilios Roussis,
we have also been able to characterise the antibacterial activities of marine plants,
particularly compounds of the diterpene class that display promising levels of
antibacterial activity against MRSA and S. aureus strains. Work on the antibacterial
properties of Cannabis sativa showed that some of the main cannabinoids display
excellent potency towards drug-resistant variants of S. aureus and support the
ancient medicinal usage of Cannabis as an anti-infective and wound healing
preparation. The acylphloroglucinol class of plant natural products are also
noteworthy, particularly from Hypericum and Mediterranean medicinal plant species
such as Myrtle (Myrtus communis), again with MIC values reaching 1 mg/L against
pathogenic bacteria. We synthesised some of these acylphloroglucinols and made
analogues and not surprisingly, were unable to improve the activity as nature really
is the best chemist of all.
The final section describes early and continuing research into the isolation and
structure elucidation of natural products from plants and microbes. The rationale for
this research is manifold: training for isolation to understand the medicinal use of a
plant or microbe, chemotaxonomic investigations, the ecological relevance of
phytochemicals in plants that are halophytic and xerophytic and in some cases just
plain academic curiosity. These studies use classical phytochemical techniques to
isolate and determine the structures of the species of investigation and where
possible, absolute stereochemistry is undertaken. It should be noted however that
isolation can be exceptionally challenging and frustrating. This can be due to the
paucity of biomass, low concentrations of compounds, complexity of the resulting
natural product mixtures and finally a lack of chemical stability of the products. All of
these issues need to be faced before structure determination can even be
attempted. A word of caution is therefore needed to the young natural product
chemist embarking on their first isolation project. However, words of encouragement
are also needed: the isolation of new, chemically complex and exquisitely biologically
active molecules is a beautiful endeavour and exceptionally rewarding on many
levels