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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, June 2001, p. 1746-1750, Vol. 45, No. 6
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.6.1746-1750.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
In Vitro Activities of Antibiotics against
Plasmodium falciparum Are Inhibited by Iron
Bruno
Pradines,*
Christophe
Rogier,
Thierry
Fusai,
Joel
Mosnier,
William
Daries,
Eric
Barret, and
Daniel
Parzy
Unité de Parasitologie, Institut de
Médecine Tropicale du Service de Santé des
Armées, Le Pharo, 13998 Marseille, France
Received 12 January 2001/Returned for modification 20 February
2001/Accepted 19 March 2001
 |
ABSTRACT |
The in vitro activities of cyclines (tetracycline,
doxycycline, minocycline, oxytetracycline, and rolitetracycline),
macrolides (erythromycin, spiramycin, roxithromycin, and
lincomycin), quinolones (norfloxacin and ofloxacin), rifampin,
thiamphenicol, tobramycin, metronidazole, vancomycin, phosphomycin, and
cephalosporins (cephalexin, cefaclor, cefamandole, cefuroxime,
ceftriazone, cefotaxime, and cefoxitin) were evaluated on
Plasmodium falciparum clones, using an isotopic,
micro-drug susceptibility test. Only tetracyclines, macrolides,
quinolones, and rifampin demonstrated in vitro activity against
P. falciparum, which increased after a prolonged exposure (96 or 144 h). In the presence of iron (FeCl3), only
the activities of tetracyclines and norfloxacin were decreased. Their
in vitro activity against intraerythrocytic stages of
multidrug-resistant P. falciparum and their efficacy in
vivo favor the use of antibiotics as antimalarial drugs. However, due
to their slow antimalarial action and to the fact that they act better
after prolonged contact, they probably need to be administered in
conjunction with a rapidly acting antimalarial drug, such as a short
course of chloroquine or quinine.
| |
INTRODUCTION |
Two of the current options to reduce
the morbidity and mortality of malaria are chemoprophylaxis and
chemotherapy. During the past 20 years, strains of Plasmodium
falciparum have become resistant to chloroquine and other
antimalarial drugs (49, 53). The search for effective
alternative antimalarial drugs with minimal side effects has stimulated
work on the identification of novel chemotherapeutic targets
(36).
In the past, the use of antibiotics has controlled antimalarial
drug-resistant strains. Thirty years ago, tetracyclines
were found to have antimalarial activity (43).
Experimental observations obtained in vitro (3, 40) and in
clinical studies (4, 16) proved the antimalarial activity
of doxycycline. Macrolide antibiotics, such as erythromycin and
azithromycin, also have both in vitro activity against P. falciparum (11, 13) and clinical activity (42,
48). Similarly, fluoroquinolones were also proven to have
antimalarial activity in vitro (19, 56) and in vivo
(50).
In all living organisms, iron is an essential growth element
(50). This metallic compound is needed for the catalysis
of DNA synthesis and for a variety of enzymes concerned in electron transport and energy metabolism. Iron chelation has been considered as
a suitable therapy for various infectious diseases, including malaria
(20). It is required for a large number of the parasite enzyme systems necessary for growth and proliferation, including dihydroorotate dehydrogenase for the synthesis of pyrimidines, phosphoenolpyruvate carboxykinase in CO2 fixation,
cytochrome oxidase in the mitochondrial electron transport system, and
superoxide dismutase in oxygen radical catabolism. Also, the
iron-dependent enzyme ribonucleotide reductase, a rate-limiting enzyme
in DNA synthesis, has been considered as a potential site of action for iron chelators (2, 39). Some antibiotics could repress the activity of enzymes, which are iron-dependent enzymes, such as tetracycline and the dihydroorotate dehydrogenase (23,
41).
The aim of the present study was (i) to determine the in vitro activity
of 24 antibiotics from 11 different classes on chloroquine-resistant P. falciparum strains after 48, 96, and 144 h of
exposure and (ii) to verify the iron binding capacity of the
antibiotics with an in vitro activity against P. falciparum
(tetracyclines, macrolides, quinolones, and rifampin).
| |
MATERIALS AND METHODS |
Strains of P. falciparum.
One
chloroquine-susceptible clone, 3D7 (Africa), and four chloroquine
resistant clones or strains, W2 (Indochina), Palo Alto (Uganda), FCR3
(Gambia), and Bres1 (Brazil), were maintained in culture. When required
for drug assays, cultures were synchronized by sorbitol lysis
(25). Susceptibility to antibiotics was determined after
suspension in RPMI 1640 medium (Life Technologies, Paisley, United
Kingdom) supplemented with 10% human serum (pooled from different
A+ or AB sera from nonimmune donors who did not live in the
area of malaria endemicity) and buffered with 25 mM HEPES and 25 mM NaHCO3 (hematocrit of 1.5%, parasitemia of 0.5%).
Drugs.
All the antibiotics were obtained from Sigma Chemical
Co. (St. Louis, Mo.). Stock solutions were prepared (i) in methanol for
tetracycline, doxycycline, minocycline, oxytetracycline,
erythromycin, spiramycin, roxithromycin, lincomycin, thiamphenicol,
cephamandole, cephalexin, cefuroxime, ceftriazone, cefotaxime,
cefoxitin, metronidazole, phosphomycin, and rifampin or (ii) in
dimethyl sulfoxide for ofloxacin, norfloxacin, rolitetracycline,
tobramycin, vancomycin, and cefaclor. Twofold serial dilutions were
prepared in sterile distilled water or RPMI for all these drugs. Final
concentrations were distributed in triplicate into Falcon 96-well
flat-bottom plates (Becton Dickinson, Franklin Lakes, N.J.), which were dried.
In vitro assays.
The isotopic micro drug susceptibility test
used in this study was described previously (38). For in
vitro isotopic microtests, 200 µl of the suspension of parasitized
erythrocytes (parasitemia of 0.5% for the 48-h test, 0.2% for the
96-h test, and 0.1% for the 144-h test) per well was distributed in
96-well plates predosed with antimalarial agents. Parasite growth was
assessed by adding 1 µCi of [3H]hypoxanthine with a
specific activity of 14.1 Ci/mmol (NEN Products, Dreiech, Germany) to
each well at 0 h for the 48-h exposure test, at 48 h for the
96-h exposure test, and at 96 h for the 144-h exposure test.
Plates were incubated for 48, 96, or 144 h at 37°C in an
atmosphere of 10% O2, 6% CO2, and 84%
N2 and 95% relative humidity.
The 50% inhibitory concentration (IC50), i.e., the drug
concentration corresponding to 50% of the uptake of
[3H]hypoxanthine by the parasites in drug-free control
wells, was determined by nonlinear regression analysis of log
dose-response curves. Data were analyzed after logarithmic
transformation and expressed as the geometric mean IC50
with 95% confidence intervals.
Iron-induced inhibition of antibiotic activity.
A range of
concentrations of antibacterial drugs, prepared in RPMI, were
preincubated with FeCl3 (Sigma Chemical Co.) at 500, 750, and 1,000 µM (concentrations in final test) in RPMI for 3 h.
Positive controls were determined with an iron-chelating agent, desferrioxamine (Sigma). For the in vitro microtest, 50 µl of the
complex and 150 µl of a suspension of parasitized erythrocytes (parasitemia of 0.5% and hematocrit of 1.5% in final) were
distributed in 96-well plates. The procedure was as described in above
for in vitro assays.
| |
RESULTS |
Table 1 gives the IC50s
of the different tetracyclines, macrolides, quinolones, and
rifampin shown to have antimalarial activity (<250 µM) against the
clone W2. The in vitro growth inhibition of these antibiotics was also
tested on four other P. falciparum strains: one
chloroquine-susceptible strain (3D7) and three chloroquine-resistant strains (FCR3, Palo Alto, and Bres1). Lincomycin (macrolide), tobramycin (aminoglycoside), thiamphenicol (chloramphenicol
derivative), metronidazole (imidazole derivative), vancomycin and
phosphomycin (unclassable antibiotics), cephalexin and cefaclor
(narrow-spectrum cephalosporins), cefamandole and cefuroxime
(extended-spectrum cephalosporins), ceftriazone and cefotaxime
(broad-spectrum cephalosporins), and cefoxitin (cephamycin) had
IC50s up to 800 µM against the chloroquine-resistant W2 clone.
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TABLE 1.
In vitro activity of tetracyclines, macrolides,
quinolones, and rifampin against a chloroquine-susceptible clone, 3D7,
and chloroquine-resistant strains, W2, Palo Alto, FCR3, and Bres1
|
|
As shown in Table 2, the antimalarial
activity of doxycycline, tetracycline, minocycline,
oxytetracycline, rolitetracycline, erythromycin, spiramycin,
roxythromycin, norfloxacin, ofloxacin, and rifampin was increased
in vitro after prolonged exposure.
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|
TABLE 2.
In vitro activity of tetracyclines, macrolides,
quinolones, and rifampin against the chloroquine-resistant clone W2
after 48, 96, and 144 h of contact exposure
|
|
Table 3 shows that the activities of
doxycycline, tetracycline, minocycline, oxytetracycline,
rolitetracycline, norfloxacin, and desferrioxamine were inhibited in
the presence of iron (FeCl3).
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|
TABLE 3.
In vitro activity of tetracyclines, macrolides,
quinolones, rifampin, and desferrioxamine in combination with
FeCl3 against the chloroquine-resistant clone W2 after
48 h of contact exposure
|
|
| |
DISCUSSION |
Thirty years ago, tetracycline and its derivatives were found to
have antimalarial activity (43), as demonstrated by in vitro (6, 30) and clinical (54) studies. The
IC50 for tetracyclines in our experiments was close to
those reported by other authors: 39 µM for oxytetracycline
(6), 32 µM for tetracycline (55), and 11 µM for doxycycline (40). Doxycycline and minocycline were the most potent tetracyclines. Enhanced potency may be due to
their increased lipophilicity, facilitating their entry into cells
(45). Tetracyclines tended to act slowly against malaria parasites, with an increased activity after prolonged exposure (96 and
144 h). In comparison, standard antimalarial drugs, such as the
fast-acting amino-4-quinoleines or amino alcohols, do not vary in
activity over time of contact (21). Because of the slow activity of tetracyclines, they would probably be administered in a
regimen that also included a rapidly acting drug. Tetracyclines act on
malaria parasite mitochondria, which, similar to eucaryotes, contains
70S ribosomes. Tetracycline also inhibits protein synthesis on 80S
ribosomes in broken-cell preparations (8). However, a low
accumulation of tetracycline is observed, which is consistent with a
mitochondrial effect (12). If tetracycline had attained high intraparasitic concentrations, 80S ribosomal inhibition could play
a role in the antimalarial effect. Tetracycline acts on mitochondria (22) and depresses the activity of dihydroorotate
dehydrogenase, an iron-dependent enzyme of the pyrimidine pathway in
P. falciparum (23, 41), presumably due to the
inhibition of enzyme protein synthesis. Doxycycline reduces the
levels of malaria nucleoside 5'-triphosphates and deoxynucleoside
5'-triphosphates (58) and has shown inhibitory effects
against preerythrocytic stages (28). Tetracyclines could
also act on the dihydroorotate dehydrogenase enzyme by chelating its
iron center. The efficacy of doxycycline alone (17, 52) or
in combination with mefloquine (27) or atovaquone
(26) in prevention or treatment of falciparum malaria has
been confirmed.
The IC50s of norfloxacin, which were similar to those
reported by other authors (in 48-h drug exposure tests) (19,
32), and ofloxacin in our experiments confirm that quinolones
are potent against P. falciparum. Norfloxacin is
approximately twice as potent in vitro than is ofloxacin and is
effective against both chloroquine-susceptible and
chloroquine-resistant parasites, more so after prolonged exposure (96 or 144 h) (56). The mode of action of
quinolones against Plasmodium species is still unknown.
However, these agents act against bacteria through inhibition of DNA
gyrase, a prokaryotic type II topoisomerase (29).
Nevertheless, the relatively slow antimalarial action of
fluoroquinolones limits their clinical application in treating
falciparum malaria. Consequently, quinolones could be used as
alternatives as part of a combination therapy.
Macrolides, such as erythromycin, were shown to be active against
P. falciparum (21, 44). The IC50 of
erythromycin in our experiments was close to those reported by other
authors, 68 µM (13). Erythromycin is active against the
chloroquine-resistant strains (IC50, 17 to 40 µM) but
seems to be inactive against the chloroquine-susceptible clone
(IC50, >250 µM). In contrast, erythromycin is inactive
against chloroquine- and quinine-resistant malaria in Thailand
(37). Azithromycin, a new macrolide antibiotic with a
longer half-life and a better bioavailability, has microbiological and
pharmacokinetic advantages over erythromycin (7).
The antimalarial activity of azithromycin has been demonstrated
against P. falciparum (13), P. yoelii (1, 14), and P. cynomolgi
(42) and in clinical studies (24). Malaria
could be a future indication for macrolides (47), although
they would be better used as part of a combination therapy
(35). In our experiments, macrolide activities were
increased in vitro during prolonged exposure, the same as for
azithromycin (57).
Rifampin was the most potent of the antibiotics tested in this study.
The IC50 of rifampin in our experiments was close to those
reported by other authors: greater than 2 µM (46). A
putative prokaryote-like RNA polymerase in P. falciparum has
been suggested as one possible target of rifampin (10). A
fixed combination of rifampin, co-trimoxazole, and isoniazid was found
to be highly effective for the treatment of malaria (9,
15). Rifampin was found to be more active after prolonged
exposure, in contrast to the results of Divo et al. (6).
Only the activities of the tetracyclines and norfloxacin were inhibited
by iron. Inhibition of activity was more pronounced for minocycline and
oxytetracycline. The ratio of the antibiotic IC50 with
FeCl3 to that of the antibiotic IC50 without
FeCl3 was greater than 2 for minocycline combined with 750 µM FeCl3 and for oxytetracycline combined with 1,000 µM
FeCl3. The IC50 of desferrioxamine was 4- to
>10-fold higher when combined with FeCl3. The reversal of
the inhibition of growth obtained by doxycycline, tetracycline,
rolitetracycline, and norfloxacin combined with FeCl3 was
weaker than that obtained with minocycline, oxytetracycline, and
desferrioxamine. With the latter antibiotics, the IC50 was not influenced by FeCl3 at 500 to 1,000 µM. Using a
siderophore colorimetric assay, doxycycline and minocycline were found
to have a strong iron-chelating activity, whereas that of tetracycline was less pronounced (18). However, Grenier et al.
(18) found that the interaction between iron and
doxycycline or tetracycline appears not to strongly affect the
antibacterial activity. Miles and Maskell concluded that the complexing
of tetracycline with iron in vivo did not affect the efficacy of
tetracycline but, rather, diminished the iron-induced enhancement of
the infection (33, 34). In our study, we showed that
FeCl3 decreased in vitro activity of tetracyclines and
norfloxacin, like the iron-chelating agent desferrioxamine. In
addition, tetracycline can complex with oxovanadium(IV)
(5). As a result, the efficacy of tetracyclines used as
antimalarial or antibacterial agents could be reduced in patients with
iron overload. Also, the combination of tetracyclines with compounds
which require iron for their antimalarial activities, such as
artemisinin and its derivatives (31), may be unadvisable. Nevertheless, the efficacy of doxycycline combined with artemether in
prevention or treatment of multidrug-resistant falciparum malaria has
been confirmed, but recrudescence was observed in 47% of patients (35). The cure rate of the artemether-doxycycline regimen
was significantly lower than that of the mefloquine-doxycycline regimen (80 and 96%), respectively (27). The efficacy of
tetracyclines may be increased if they were combined with iron chelators.
The present study clearly demonstrated the in vitro activity of
antibacterial drugs (tetracyclines, macrolides, quinolones, and
rifampin) against P. falciparum. Their in vitro activity
against intraerythrocytic stages of multidrug-resistant P. falciparum and their efficacy in vivo favor the use of antibiotics
as antimalarial drugs. However, because of their relatively slow
antimalarial action and enhanced activity after prolonged contact, they
would be best administered in conjunction with a rapidly acting
antimalarial drug, such as a short course of chloroquine or quinine. In
addition, we showed that the activities of tetracyclines and
norfloxacin may be decreased in the presence of FeCl3, in
favor of a combination with iron chelators.
| |
ACKNOWLEDGMENTS |
This work was supported by the Délégation
Générale pour l'Armement (DGA; contrat d'objectif
9810060), the Groupe de Recherche en Parasitologie (GDR) 1077, and the
Direction Centrale du Service de Santé des Armées.
We thank D. Walliker (Cell Animal and Population Biology, Edinburgh,
United Kingdom), W. K. Milhous (Walter Reed Army Institute of
Research, Washington, D.C.), and J. Gysin (Laboratoire de Parasitologie Expérimentale, Marseille, France) for clones and strains. We are
grateful to Alain Buguet and to Valerie Brown-Buguet for constructive editorial comments.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: IMTSSA,
Unité de Parasitologie, Bd Charles Livon, Parc le Pharo, BP 46, 13998 Marseille Armées, France. Phone: 33 4 91 15 01 10. Fax: 33 4 91 15 01 64. E-mail: bruno.pradines{at}free.fr.
| |
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Antimicrobial Agents and Chemotherapy, June 2001, p. 1746-1750, Vol. 45, No. 6
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.6.1746-1750.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
