8 research outputs found
Anti-mycobacterium tuberculosis activity of polyherbal medicines used for the treatment of tuberculosis in Eastern Cape, South Africa.
Background: The emergence of drug-resistant strains of Mycobacterium
tuberculosis has become a global public health problem. Polyherbal
medicines offer great hope for developing alternative drugs for the
treatment of tuberculosis. Objective: To evaluate the anti-tubercular
activity of polyherbal medicines used for the treatment of
tuberculosis. Methods: The remedies were screened against Mycobacterium
tuberculosis H37Rv using Middlebrook 7H9 media and MGIT BACTEC 960
system. They were liquid preparations from King Williams Town site A
(KWTa), King Williams Town site B (KWTb), King Williams Town site C
(KWTc), Hogsback first site (HBfs), Hogsback second site (HBss),
Hogsback third site (HBts), East London (EL), Alice (AL) and Fort
Beaufort (FB). Results: The susceptibility testing revealed that all
the remedies contain anti-tubercular activity with KWTa, KWTb, KWTc,
HBfs, HBts, AL and FB exhibiting more activity at a concentration below
25 \ub5l/ml. Furthermore, MIC values exhibited inhibitory activity
with the most active remedies from KWTa, HBfs and HBts at 1.562
\ub5g/ml. However, isoniazid showed more inhibitory activity against
M. tuberculosis at 0.05 \ub5g/ml when compare to the polyherbal
remedies. Conclusion: This study has indicated that these remedies
could be potential sources of new anti-mycobacterial agents against M.
tuberculosis. However, the activity of these preparations and their
active principles still require in vivo study in order to assess their
future as new anti-tuberculosis agents
Elucidation of the mode of action of a furanone based antituberculosis compound
Thesis (PhD)--Stellenbosch University, 2012.ENGLISH ABSTRACT: The prevalence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium
tuberculosis has been increasing to alarming levels globally. This has been exacerbated by
tuberculosis (TB) co-infection with HIV where the epidemic is endemic. South Africa as a developing
country is hit hard by TB and efforts to develop TB drugs that are compatible with anti-retroviral
medication and also effective against MDR/XDR, could help shorten the treatment duration of the
current TB treatment regimens. This thesis presents the identification and characterisation of a novel
furanone based compound (F1082) and its derivatives as leads for anti-TB drug development.
Furanones are generally known for an array of biological activities ranging from antibacterial,
antifungal and antitumor. F1082 has an aromatic benzene structure and was identified from screening synthetic compounds
against M. tuberculosis. It is potent against M. tuberculosis at minimum inhibitory concentration
(MIC) of 8 μg/ml. It is selective for mycobacteria since it did not inhibit the growth of Gram-positive
and Gram-negative bacteria at concentrations five times the MIC for M. tuberculosis. F1082 is
generally bacteriostatic around MIC concentrations in its effects against M. tuberculosis however; it
may be bactericidal at higher concentrations. It is as effective against MDR, XDR and clinical isolates
of M. tuberculosis at the same concentration as the M. tuberculosis H37Rv reference strain. This
suggests that F1082 may have a different mechanism of action compared to current TB drugs. It has
been shown to have no antagonistic effect with the first-line anti-TB drugs and it has been shown to
synergize with rifampicin by reducing the MIC of rifampicin. A drawback of F1082 is that it is
cytotoxic to human cell lines, but this is presently being addressed through the synthesis of analogues
that have shown improved activity and less cytotoxicity. The synthesis of more than 40 analogues has
led to identification of 4 compounds that have more than five times higher activity and more than 100
times less cytotoxicity against human cell-lines. Microarray analyses have identified possible metabolic pathway/s in M. tuberculosis that is/are
affected by F1082. One subset of genes which showed the most prominent alteration encodes the
siderophores, which are involved with iron homeostasis in the M. tuberculosis bacillus. Of these
genes, 7 were of interest (mbtB, mbtC, mbtD, mbtE, mbtF, mbtH and bfrB) as they all fall in the same
cluster and are involved in iron acquisition. Due to the involvement of iron we also show that F1082
generates oxidative stress that is metal (iron) dependent. From the results we conclude that F1082 is a
promising antituberculosis lead compound with unique target properties and also specificity against
mycobacteria.AFRIKAANSE OPSOMMING: Die voorkoms van veelvuldige middelweerstandige M.tuberculosis (MDR) en uiters
middelweerstandige M.tuberculosis (XDR) is besig om toe te neem teen ‘n kommerwekkende tempo
wêreldwyd. Hierdie situasie word vererger met die ko-infektering van M.tuberculosis en HIV. Suid-
Afrika, as ontwikkelende land, word sleg benadeel met tuberkulose siekte. Antituberkulose middels
wat kan saamwerk met bestaande antiretrovirale middels en ook effektief is teen MDR en XDR
stamme, kan alles meewerk om die behandelingstyd van tuberkulose te verkort. In hierdie tesis
identifiseer en karakteriseer ons ‘n furanoon-gebaseerde verbinding (F1082) en derivate daarvan as
voorloper-middels vir anti-tuberkulose middelontwikkeling. Furanone is algemeen bekend vir ‘n
verskeidenheid van biologiese aktiwiteite insluitende antibakteriële-, antifungale- en antitumor
aktiwiteite.
F1082 bevat ‘n aromatiese benseenstruktuur en is oorspronklik geïdentifiseer gedurende die
skandering van sintetiese middels teen M.tuberculosis. Dit het ‘n sterk werking teen M.tuberculosis
met ‘n minimum inhibitoriese konsentrasie (MIC) van 8ug/ml. Dit is baie selektief vir mikobakterieë
aangesien dit nie gram-positiewe of gram-negatiewe bakterieë teen 5 maal die MIC, soos vir
M.tuberculosis, geïnhibeer het nie. F1082 is bevind om, by laer konsentrasies, bakteriostaties te wees in sy aktiwiteit teen M.tuberculosis maar by hoër konsentrasies word ‘n meer bakteriosidiese effek
waargeneem. F1082 is effektief teen MDR, XDR en kliniese isolate van M.tuberculosis en teen
dieselfde konsentrasie soos vir die M. tuberculosis H37Rv verwysingstam waargeneem is. Dit
impliseer dat F1082 dalk ‘n alternatiewe meganisme van werking het in vergelyking met die van die
huidige TB teenmiddels. F1082 toon geen antagonistiese werking in kombinasie met die voorste anti-
TB middels nie, maar toon wel sinergistiese werking in kombinasie met rifampisien. F1082 toon nog
sitotoksiese aktiwiteit teenoor menslike sellyne, maar die sintese van derivate van F1082 toon tot
dusvêr groter anti-TB aktiwiteit en verminderde sitotoksisiteit. Die sintese van meer as 40 homoloë
het gelei tot die identifisering van vier verbindings met vyf keer hoër anti-TB aktiwiteit en honderd
keer verminderde sitotoksisiteit teen menslike sellyne as F1082 self.
“Microarray” ontledings het ‘n aantal metabolise paaie geïdentifiseer waar F1082 ‘n effek kan
uitoefen. Een stel gene wat die mees uitstaande effek toon kodeer vir siderofore wat betrokke is by
yster homeostase in M.tuberculosis. Van hierdie gene was daar sewe van belang omdat hulle in
dieselfde groep voorkom en almal betrokke is by ysteropname (mbtB, mbtC, mbtD, mbtE, mbtF,
mbtH, bfrB). Weens die rol wat F1082 in ysterhomeostase speel, toon ons ook dat F1082
intrasellulêre oksidatiewe stres bevorder wat yster afhanklik is. Al ons resultate dui daarop dat F1082
‘n belowende ant-TB voorloper verbinding is met spesifisiteit teen M.tb en unieke teikeneienskappe in
M. tuberculosis
Development of novel anti-tuberculosis drugs from African medicinal plants
Includes bibliographical references (leaves 55-63)
Anti-mycobacterium tuberculosis activity of polyherbal medicines used for the treatment of tuberculosis in Eastern Cape, South Africa
CITATION: amewo, E. B., et al. 2017. Anti-mycobacterium tuberculosis activity of polyherbal medicines used for the treatment of tuberculosis in Eastern Cape, South Africa. African Health Sciences, 17(3): 780-789, doi:10.4314/ahs.v17i3.21.The original publication is available at https://www.ajol.info/index.php/ahs/indexBackground: The emergence of drug-resistant strains of Mycobacterium tuberculosis has become a global public health problem.
Polyherbal medicines offer great hope for developing alternative drugs for the treatment of tuberculosis.
Objective: To evaluate the anti-tubercular activity of polyherbal medicines used for the treatment of tuberculosis.
Methods: The remedies were screened against Mycobacterium tuberculosis H37Rv using Middlebrook 7H9 media and MGIT BACTEC
960 system. They were liquid preparations from King Williams Town site A (KWTa), King Williams Town site B (KWTb),
King Williams Town site C (KWTc), Hogsback first site (HBfs), Hogsback second site (HBss), Hogsback third site (HBts), East
London (EL), Alice (AL) and Fort Beaufort (FB).
Results: The susceptibility testing revealed that all the remedies contain anti-tubercular activity with KWTa, KWTb, KWTc,
HBfs, HBts, AL and FB exhibiting more activity at a concentration below 25 μl/ml. Furthermore, MIC values exhibited inhibitory
activity with the most active remedies from KWTa, HBfs and HBts at 1.562 μg/ml. However, isoniazid showed more
inhibitory activity against M. tuberculosis at 0.05 μg/ml when compare to the polyherbal remedies.
Conclusion: This study has indicated that these remedies could be potential sources of new anti-mycobacterial agents against
M. tuberculosis. However, the activity of these preparations and their active principles still require in vivo study in order to assess
their future as new anti-tuberculosis agents.https://www.ajol.info/index.php/ahs/article/view/161253Publishers' Versio
Preliminary evaluation of artemisinin–cholesterol conjugates as potential drugs for the treatment of intractable forms of malaria and tuberculosis
To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin–cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC50) against Pf drug‐sensitive NF54, and drug‐resistant K1 and W2 strains ranged from 0.03–2.6, 0.03–1.9, and 0.02–1.7 μm. Although the compounds are less active than the precursor artemisinin derivatives, the cholesterol moiety renders the compounds relatively insoluble in the culture medium, and variation in solubilities among the different compounds may reflect in the range of efficacies observed. Activities against Mtb H37Rv were assessed using a standardized colony‐forming unit (CFU) assay after 24 h pretreatment of cultures with each of the compounds. Percentage inhibition ranged from 3–38 % and 18–52 % at 10 and 80 μm, respectively. Thus, in contrast to the comparator drug artemether, the conjugates display enhanced activities. The immediate aims include the preparation of conjugates with enhanced aqueous solubilities, assays against malaria and TB in vivo, and for TB, assays using an infected macrophage model and assessment of granuloma influx.The South African Medical Research Council (MRC) with funds from the National Treasury under its Economic Competitiveness and Support Package. The South African National Research Foundation (NRF) is thanked for financial support to R.K.H. (NRF UIDs 90682 and 98934). H.N.W., F.S., J.F.W., D.D.N., and R.K.H. also thank the North‐West University for financial support.https://onlinelibrary.wiley.com/journal/18607187hj2019Biochemistr