Introduction

The last report of the World Health Organisation (WHO) on malaria worldwide indicates that there was an increased case incidence of malaria between 2020 and 2021 due to the disruption to services during the Covid-19 pandemic with almost 241 million malaria cases and 627,000 deaths in 85 malaria-endemic countries (WHO, 2021). This observation supports that malaria is still among the most harmful parasitic diseases and a major public health problem in several tropic and subtropic regions of the world, especially the developing countries which are poorly deserved with equipped medical centres and where the resistance of Plasmodium falciparum to the prescribed antimalarial drugs have been reported (Nasomjai, Arpha, Sodngam, & Brandt, 2014; Ogbole, Segun, Akinleye, & Fasinu, 2018). Plasmodium falciparum is the most virulent parasite that causes the most severe forms of malaria and the highest rate of mortality with children and pregnant women as the most affected people (Júnior et al., 2012). Several strategies have been proposed by WHO in preventing and curing the diseases over the last decades, including the combination of effective therapeutic agents like artemisinin-based combination therapy (ACT), the large distribution of long-lasting insecticide-treated bed nets or the development of new insecticides to eliminate its malaria mosquito vectors (Happi et al., 2015; Happi et al., 2022). However, new more potent antimalarial drugs are needed to supply the ones existing already and address the observed resistance (Bathurst & Hentschel, 2006). Until 2006, four main classes of compounds have been identified among the most prescribed antimalarial drugs: The quinine derivatives like chloroquine, mefloquine, amodiaquine or the aminoquinolines like primaquine; the antifolate compounds like pyrimethamine, dapsone or sulfadoxine, the artemisinin derivatives like artesunate, artemether or co-Artem; and finally the hydroxynaphthoquinone like atovaquone (Baniecki, Wirth, & Clardy, 2007). In this regard for new antiplasmodial drug discovery, it seems imperative to explore new sources of bioactive metabolites with new structural diversity to increase the opportunities in structure modifications as well as in the development of a high number of possibilities of active compounds.

The bacteria called Streptomyces represent an interesting source of specialized metabolites with a high structural diversity and a large scale of biological activities. It is well reported that mostly produced antibiotics like chloramphenicol from Streptomyces venezuelae and used in the treatment of typhoid, rifampicin and vancomycin from S. mediterranei and S. orientalis, respectively, and which have been important antibiotics prescribed in the treatment of leprosy and methicillin-resistant Staphylococcus aureus, respectively (Chater, 2006). Many of these antibiotics derived from Streptomyces are highly functionalised compounds that mostly belong to the class of macrolides or cyclopolypeptides. Like other microorganisms (fungi or bacteria) which live in their hosts (Happi et al., 2015), Streptomyces can be isolated from plant material, soil or marine sources like sea plant, sea sediment or sea animals. Our literature survey provided us with significant data on the high structural diversity and strong activity of some Streptomyces compounds compared to the well-known standard drugs and which deserve further attention in the development of new potent antimalarial drugs. To the best of our knowledge, no review article has been published on the phytochemistry and pharmacology of the bacteria Streptomyces for their contribution in fighting against malaria as a source of antiplasmodial agents. This review covers the documented works up to December 2021.

Methodology

This paper has been written based on collected data previously reported in the literature over the last decades up to 2021. Numerous online libraries including Scifinder and Scifindern, PubMed, Google Scholar as well as Web of Science were used in searching for information on antiplasmodial metabolites from Streptomyces. The keywords Streptomyces, Plasmodium, antiplasmodial and malaria were used to monitor and refine our search without language restriction.

Antiplasmodial lead compounds from Streptomyces

The literature survey on the previous chemical and pharmacological studies of Streptomyces revealed that numerous specialized metabolites, which are mostly antibiotics, have been isolated from an important number of strains that were not fully identified in many cases but reported as Streptomyces sp. and their original strain codes from the authors' databank. The reported Streptomyces sp. have been isolated from plant material like rice (Supong et al., 2016), from marine source (Buedenbender et al., 2018; Supong et al., 2012) or from soil (Intaraudom et al., 2015; Supong et al., 2016). Among the reported compounds from Streptomyces, 70 distinct compounds have demonstrated an antiplasmodial potency including 51 natural products (~72.9 %) and 19 synthetic derivatives (~27.1 %) prepared from isolated natural products. The 51 natural occurring antiplasmodial compounds from Streptomyces can be organized into thirteen different classes of specialized metabolites sorted as follows: Macrolides were the most abundant (~23.5 %) followed by anthraquinones (~15.7 %), polypeptides (~11.7 %), geldanamycin analogues (~7.8 %), pactamycin analogues, polyether compounds and diketopiperazines (~5.9 %, each), cyclopeptides and carbazomycin analogues (~3.9 %, each), sesquiterpenoid, diterpenoid and zeatin-type compound (~2.0 %, each) and others (~9.8 %). As we recently reported, a pure compound should exhibit an IC50 ≤ 10 µM to be considered as an active compound by the industry (Happi et al., 2022).

Furthermore, the seventy reported antiplasmodial compounds from Streptomyces have been tested against a total of eight Plasmodium falciparum strains including four chloroquine-sensitive strains (P. falciparum 3D7, D6, NF54 and HB3) and four chloroquine-resistant strains (P. falciparum K1, Dd2, W2 and 7G8) (Table 1). Globally, the resistant strains K1, Dd2 and the sensitive strain 3D7 have been the most used during the antiplasmodial tests of Streptomyces compounds. Thus, the promising results against the resistant strains indicated that Streptomyces can be an important source of active principles to handle the resistance of P. falciparum which represent the main issue in controlling the progress and the eradication of malaria (Happi et al., 2022). Artemisinin (1) and its derivatives dihydroartemisinin (2) and artesunate (3), as well as the gold antimalarial drug chloroquine (4) and other standard drugs like mefloquine (5), puromycin (6), pyrimethamine (7) and pyronaridine (8), have been used as reference compounds (standards) during the reported investigations (Figure 1). Their potencies against the used strains of P. falciparum are compiled in Table 1.

Figure 1

Some drugs used as standard for antiplasmodial tests.

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Table 1

Potencies of standard drugs used during the recorded antiplasmodial tests.

Type of P. falciparum

Strains index

Standard, IC50

Reference

CQ-sensitive strains

3D7

Artesunate (3), 0.9 nM

(Kiefer et al., 2019)

Chloroquine (4), 3.4 nM

(Buedenbender et al., 2018)

Dihydroartemisinin (2), 0.4 nM

Puromycin (6), 148.9 nM

Pyrimethamine (7), 4.7 nM

Pyronaridine (8), 7.4 nM

D6

Chloroquine (4), 10.6 nM

(Almabruk et al., 2013)

NF54

Chloroquine (4), 6 nM

(Happi et al., 2015)

HB3

Chloroquine (4), 9.47 nM

(Baniecki et al., 2007)

Mefloquine (5), 9.63 nM

Artemisinin (1), 9.70 nM

CQ-resistant strains

K1

Artemisinin (1), 3.9 nM

(Isaka, Jaturapat, Kramyu, Tanticharoen, & Thebtaranonth, 2002)

Chloroquine (4), 0.46 uM

(Jang et al., 2017)

Dihydroartemisinin (2), 1.98 nM

(Intaraudom et al., 2015)

Mefloquine (5), 29.1 nM

(Supong et al., 2016)

Dd2

Artesunate (3), 1.3 nM

(Buedenbender et al., 2018)

Chloroquine (4), 87.9 nM

Dihydroartemisinin (2), 0.6 nM

Puromycin (6), 114.4 nM

Pyronaridine (8), 8.3 nM

7G8

Chloroquine (4), 89.5 nM

(Almabruk et al., 2013)

W2

Chloroquine (4), 70 nM

(Mackinnon, Durst, & Arnason, 1997)

[i] CQ: chloroquine

The reported active compounds from Streptomyces can be classified into five categories based on their potencies in comparison with the criteria for antiplasmodial activity against P. falciparum used by the World Health Organization that indicates that : Pronounced activity (IC50 < 5 μg/ml or IC50 ≤ 0.1 μM) ; good activity (5 < IC50 <10 μg/ml or IC50 > 0.1 μM but ≤ 5 μM); moderate activity (10 < IC50 < 20 μg/ml or IC50 > 5 μM but < 20 μM) ; low activity (20 < IC50 < 40 μg/ml or IC50 > 20 μM but < 50 μM) and inactive if IC50 > 40 μg/ml or IC50 > 50 μM (WHO 2022; ) (Happi et al., 2022).

Macrolides

Macrolides represent an important class of antibiotics isolated from microorganisms including the most famous ones azithromycin and erythromycin which are pharmaceutical drugs available on market. Through the last decades, the chemical investigations of several Streptomyces strains led to the isolation and characterization of a number of macrolides including nineteen which were identified as potent antiplasmodial agents according to the data available in the literature so far (Table 2, Figure 2).

Figure 2

Antiplasmodial macrolides from Streptomyces.

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Table 2

Antiplasmodial macrolides from Streptomyces.

Name

Strain, IC50

Source

Reference

9

Bafilomycin A1

K1, 0.041 μg/ml

S. spectabilis BCC 4785

(Isaka et al., 2002)

10

Concanamycin A

K1, 0.2 nM

Streptomyces sp.

(Auparakkitanon & Wilairat, 2006)

11

Samroiyotmycin A

K1, 3.65 μg/ml

Streptomyces sp. BCC33756

(Dramae et al., 2013)

12

Samroiyotmycin B

K1, 3.16 μg/ml

13

Efomycin M

K1, 5.23 μg/ml

Streptomyces sp. BCC72023

(Supong et al., 2016)

14

Efomycin G

K1, 2.37 μg/ml

Streptomyces sp. BCC72023

(Supong et al., 2016; Supong et al., 2016)

Streptomyces sp. BCC71188

15

oxohygrolidin

K1, 2.30 μg/ml

Streptomyces sp. BCC72023

(Supong et al., 2016)

16

Monoglycosylelaiolide

K1, 2.46 μg/ml

Streptomyces sp. BCC71188

(Supong et al., 2016)

17

Elaiophylin (or azalomycin)

K1, 0.22 μg/ml

18

11,11′-Odimethylelaiophylin

K1, 1.47 μg/ml

19

Oxohygrolidin

K1, 2.30 μg/ml

20

Elaiophylin

3D7, 777.9 nM

Streptomyces sp. USC-16018

(Buedenbender et al., 2018)

Dd2, 598.5 nM

Earlier in 2002, the bacterial strain Streptomyces spectabilis BCC4785 has been isolated from the soil sample and the bio-guided fractionation of its extract led to the isolation of the macrolide bafilomycin A1 (9) showing a significant activity (IC50 = 0.041 μg/ml) against Plasmodium falciparum K1 (Isaka et al., 2002). Later in 2006, another macrolide named concanamycin A (10) from Streptomyces sp. displayed a strong antiplasmodial activity supported by its IC50 of 0.2 nM against P. falciparum K1 (Auparakkitanon et al., 2006). Two 20-membered macrolides samroiyotmycins A (11) and B (12) were reported from Streptomyces sp. BCC33756 and tested for their antiplasmodial potency which gave the IC50 values of 3.65 μg/ml and 3.16 μg/ml, respectively, against P. falciparum K1 (Dramae et al., 2013).

In 2016, Supong and co-workers have isolated the strain BCC72023 of Streptomyces sp. from Oryza sativa (rice). Its screening for antiplasmodial compounds gave the identification of three macrolides namely efomycin M (13) reported for the first time from a natural source, efomycin G (14) and oxohygrolidin (15) which displayed interesting potency against P. falciparum K1 with IC50 values of 5.23 μg/ml, 2.37 μg/ml and 2.30 μg/ml, respectively (Supong et al., 2016). Within the same year, the same authors reported five additional macrolides from the terrestrial Streptomyces sp. BCC71188 including monoglycosylelaiolide (16), elaiophylin also called azalomycin (17), 11,11′-odimethylelaiophylin (18), oxohygrolidin (19) and the previously-reported efomycin G (14) which displayed significant antiplasmodial activity against P. falciparum K1 with IC50 values of 2.46 μg/ml, 0.22 μg/ml, 1.47 μg/ml, 2.30 μg/ml and 2.37 μg/ml, respectively (Supong et al., 2016).

Most recently in 2018, elaiophylin (20) has been reported from Streptomyces sp. USC-16018 with an IC50 of 777.9 nM with 96.6% inhibition at 40 μM against the chloroquine-sensitive strain P. falciparum 3D7 while it showed a more relevant activity against P. falciparum Dd2 with an IC50 of 598.5 nM with 86.1% inhibition at 40 μM (Buedenbender et al., 2018).

Furthermore, six macrolides have been partially characterized as high functionalized compounds which showed interesting antiplasmodial activity. Briefly, munumbicins A‒D isolated from Streptomyces NRRL30562 demonstrated strong antiplasmodial activity against P. falciparum CSC-1 (Honduras) with very low IC50 values of 175 ng/ml, 130 ng/ml, 6.5 ng/ml and 4.5 ng/ml, respectively. More interestingly, the potency of munumbicin D was determined as almost 50% above that of the standard chloroquine and it did not show any observable lysis of human red blood cells up to a concentration of 80 μg/ml which qualified munumbicin D as a good candidate for the development of new malarial drugs (Castillo et al., 2002). Moreover, the same authors characterized two other munumbicins (E-4 and E-5) from Streptomyces NRRL3052 which were less potent than the previous ones with IC50 values of 0.50 μg/ml and 0.87 μg/ml, respectively, against the same strain of P. falciparum CSC-1 (Honduras) (Castillo et al., 2006).

Polypeptides

Besides the macrolides, another important class of antibiotics from natural sources is represented by the cyclopolypeptides also designated as polyketides. They consist of an association of several amino acids (or peptide) units which can be cyclic or acyclic. Depending on the number of units, we can distinguish different subclasses of polypeptides. For instance, the literature survey indicated that six natural occurring antiplasmodial polypeptides including two hexadepsipeptides (21 and 22), two heptadepsipeptides (23 and 24) and two octadepsipeptides (42 and 43) have been reported from Streptomyces strains (Table 3 , Figure 3). Furthermore, seventeen new synthetic analogues (2541) with significant potencies have been prepared from desoxycyclomarin C (24).

Figure 3

Antiplasmodial polypeptides from Streptomyces.

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Table 3

 Antiplasmodial polypeptides from Streptomyces.

Name

Strain, IC50

Source

Reference

21

Mollemycin A

3D7, 7 nM

Streptomyces sp. (CMBM0244)

(Raju et al., 2014)

Dd2, 9 nM

22

Valinomycin

NF54, 3.75 ng/ml

Streptomyces sp. PR3

(Watson et al., 2021)

23

Cyclomarin C

K1, 0.24 μg/ml

Streptomyces sp. BCC26924

(Intaraudom, Rachtawee, Suvannakad, & Pittayakhajonwut, 2011)

24

Desoxycyclomarin C

3D7, 39.8 nM

Streptomyces sp. CNB-982

(Kiefer et al., 2019)

25

Compound 25a

3D7, 9.0 nM

Synthetic analogue

Dd2, 12.9 nM

26

Compound 25b

3D7, 4.4 nM

Synthetic analogue

Dd2, 6.5 nM

27

Compound 25c

3D7, 47.8 nM

Synthetic analogue

Dd2, 76.0 nM

28

Compound 25d

3D7, 13.4 nM

Synthetic analogue

Dd2, 17.8 nM

29

Compound 25e

3D7, 28.1 nM

Synthetic analogue

Dd2, 27.5 nM

30

Compound 28a

3D7, 34.4 nM

Synthetic analogue

Dd2, 71.8 nM

31

Compound 28b

3D7, 57.6 nM

Synthetic analogue

Dd2, 200.2 nM

32

Compound 28c

3D7, 355.7 nM

Synthetic analogue

Dd2, 300.3 nM

33

Compound 28d

3D7, 230.3 nM

Synthetic analogue

Dd2, 256.7 nM

34

Compound 28e

3D7, 314.2 nM

Synthetic analogue

Dd2, 421.5 nM

35

Compound 34a

3D7, 47.9 nM

Synthetic analogue

Dd2, 36.7 nM

36

Compound 34b

3D7, 452.0 nM

Synthetic analogue

Dd2, 346.5 nM

37

Compound 34c

3D7, 177.5 nM

Synthetic analogue

Dd2, 287.8 nM

38

Compound 34d

3D7, 362.4 nM

Synthetic analogue

Dd2, 318.4 nM

39

Compound 35a

3D7, 303.5 nM

Synthetic analogue

Dd2, 260.8 nM

40

Compound 35b

3D7, 428.5 nM

Synthetic analogue

Dd2, 305.1 nM

41

Compound 35e

3D7, 287.4 nM

Synthetic analogue

Dd2, 196.7 nM

42

Octaminomycin A

3D7, 1.5 μM

Streptomyces sp. RK85-270

(Jang et al., 2017)

Dd2, 1.6 μM

K1, 1.3 μM

43

Octaminomycin B

3D7, 1.5 μM

Dd2, 1.1 μM

K1, 0.85 μM

Among the antiplasmodial hexadepsipeptides reported so far from Streptomyces, mollemycin A (21) is the first glyco-hexadepsipeptide-polyketide isolated from Streptomyces sp. CMBM0244 and demonstrating an exceptional potency against the drug-sensitive P. falciparum 3D7 and the multidrug-resistant P. falciparum Dd2 with IC50 values of 7 nM and 9 nM, respectively (Raju et al., 2014), whereas the recent works ofWatson et al. (2021) supported that valinomycin (22) obtained from Streptomyces sp. PR3 displayed potent activity (IC50 of 3.75 ng/ml) in a single test against P. falciparum NF54, while more interestingly, they found that the activity was increasing in a mixed test when valinomycin was mixed in different ratios with cyclic polypropylene glycols (cPPG). A series of tests revealed that when the cPPG fraction showed an activity of 1792 ng/ml, but the mixtures 22+cPPG in the fixed ratio 4:1, 3:2, 2:3 and 1:4 will display an increased potency of 1.86 ng/ml, 0.90 ng/ml, 0.75 ng/ml and 0.53 ng/ml, respectively. Their study supported that cPPG can significantly and synergistically improve in vitro the antiplasmodial potency of valinomycin (22) (Watson et al., 2021).

Cyclomarin C (23) and desoxycyclomarin C (24) are two natural heptadepsipeptides obtained from Streptomyces sp. BCC26924 and Streptomyces sp. CNB-982, respectively. Both compounds showed strong antiplasmodial activity indicated by the IC50 value of 0.24 μg/ml for cyclomarin C (23) against P. falciparum K1 and 39.8 nM for desoxycyclomarin C (24) against P. falciparum 3D7 (Intaraudom et al., 2011; Kiefer et al., 2019). Seventeen new analogues (2541) of desoxycyclomarin C have been synthesised and tested against the strains 3D7 and Dd2 of P. falciparum. In this regard, the potencies (IC50 values) were ranging from 4.4 nM to 452.0 nM against P. falciparum 3D7 and from 6.5 nM to 421.5 nM against P. falciparum Dd2 (Table 3 ). The molecular docking performed by the authors suggested that the presence of the N'-methyltryptophan unit and the γ,δ-unsaturated side chain might play an important role in the improvement of the antiplasmodial potencies of the synthesised analogues (Kiefer et al., 2019).

Finally, two octadepsipeptides viz octaminomycins A (42) and B (43) were previously obtained from Streptomyces sp. RK85-270 and tested for their antiplasmodial activity against three P. falciparum strains including the drug-sensitive strain 3D7 and the two multidrug-resistant strains Dd2 and K1. The results showed that both compounds possessed the same activity against P. falciparum 3D7 with IC50 of 1.5 μM, while compound 42 was more active than 43 against the two other strains with IC50 values of 1.6 μM and 1.3 μM for compound 42 against P. falciparum Dd2 and K1, respectively; while compound 43 displayed IC50 values of 1.1 μM and 0.85 μM, respectively. Additionally, the two compounds were more pharmacologically interesting due to their no significant cytotoxicity against human cervical cancer cells (HeLa), human promyelocytic leukaemia cells (HL-60), mouse temperature-sensitive cdc2 mutant cells (tsFT210), and rat kidney cells that were infected with ts25 (srcts-NRK) at the highest concentration of 30 μM (Jang et al., 2017).

Anthraquinones

Four C-glycosylated benz[α]anthraquinones urdamycinones E (44) and G (45), dehydroxyaquayamycin (46) as well as urdamycin E (47) were isolated from the marine Streptomyces sp. BCC45596 and displayed potent antiplasmodial activity against P. falciparum K1 with IC50 values of 0.0534 μg/ml, 0.142 μg/ml, 2.93 μg/ml and 0.173 μg/ml, respectively (Supong et al., 2012). The comparison of the potency with their structural changes (Table 4 , Figure 4) suggested that the free angular hydroxy groups in their structures might play an important role in the activity. Furthermore, the increasing of sugar units slightly reduced the potency of the tested compounds. In addition to that four C-glycosylated benz[α]anthraquinones, four other anthraquinones have been obtained from the culture of the terrestrial Streptomyces sp. BCC27095 and identified as steffimycins B (48) and C (49), 10-dihydrosteffimycin B (50) and 7-deoxysteffimycinone (51). However, compound 49 showed strong activity against P. falciparum K1 with IC50 of 0.53 μM, while compounds 48, 50 and 51 demonstrated a good activity with IC50 values of 4.76 μM, 2.19 μM and 8.03 μM, respectively (Intaraudom et al., 2015).

Figure 4

Antiplasmodial anthraquinones from Streptomyces

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Table 4

 Antiplasmodial anthraquinones from Streptomyces.

Name

Strain, IC50

Source

Reference

44

Urdamycinone E

K1, 0.0534 μg/ml

Streptomyces sp. BCC45596

(Supong et al., 2012)

45

Urdamycinone G

K1, 0.142 μg/ml

46

dehydroxyaquayamycin

K1, 2.93 μg/ml

47

urdamycin E

K1, 0.173 μg/ml

48

steffimycin B

K1, 2.19 μM

Streptomyces sp. BCC27095

(Intaraudom et al., 2015)

49

Steffimycin C

K1, 0.53 μM

50

10-Dihydrosteffimycin B

K1, 4.76 μM

51

7-deoxysteffimycinone

K1, 8.03 μM

Geldanamycin analogues

Another important class of antiplasmodial compounds from Streptomyces is composed of geldanamycin (52) and its congeners 17-odemethylgeldanamycin (53), 17-demethoxyreblastatin (54) isolated from the terrestrial Streptomyces sp. BCC71188, as well as herbimycin G (55) obtained from the marine Streptomyces sp. USC-16018 (Supong et al. 2016b; ) (Buedenbender et al., 2018). Geldanamycin (52) and 17-demethoxyreblastatin (54) gave similar strong potencies of IC50 values 0.35 μg/ml and 0.31 μg/ml, respectively, against P. falciparum K1, while 17-odemethylgeldanamycin (54) was moderately active with an IC50 value of 1.90 μg/ml against the same parasitic strain (Table 5). More recently, the research works carried out byBuedenbender et al. (2018) dealt with the identification of herbimycin G (55) containing a geldanamycin scaffold in its structure. Compound 55 showed at 40 μM, 77.2% inhibition of P. falciparum 3D7 and 81.7% inhibition of P. falciparum Dd2 (Buedenbender et al., 2018). The structures of the antiplasmodial geldanamycin derivatives are presented in Figure 5 .

Figure 5

Antiplasmodial geldanamycin analogues from Streptomyces.

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Table 5

Antiplasmodial geldanamycin analogues from Streptomyces.

Name

Strain, IC50

Source

52

Geldanamycin

K1, 0.35 μg/ml

Streptomyces sp. BCC71188

(Supong et al., 2016)

53

17-Odemethylgeldanamycin

K1, 1.90 μg/ml

54

17-demethoxyreblastatin

K1, 0.31 μg/ml

55

Herbimycin G

3D7, 77.2 % Inhib. at 40 μM

Streptomyces sp. USC-16018

(Buedenbender et al., 2018)

Dd2, 81.7 % Inhib. at 40 μM

Pactamycin analogues

Pactamycin (56) is a well-known antibiotic discovered by the Upjohn Company in the early 1960s and has been reported during the last decades from Streptomyces pactum ATCC 27456 by Almabruk et al. (2013). During their investigations, the authors also isolated two other pactamycin analogues indexed TM-025 (57) and TM-026 (58) (Figure 6 ) which were submitted to mutasynthetic strategy to generate their fluorinated derivatives TM-025F (59) and TM-026F (60), respectively. All five compounds were screened for their antiplasmodial activity against three P. falciparum strains including the chloroquine-sensitive strain D6 and two multidrug-resistant strains Dd2 and 7G8. The results (Table 6 ) showed that pactamycin (56) was the most active compound against the three strains, while its congeners compounds 57 and 58, as well as their fluorinated derivatives 59 and 60, were slightly less active against the three strains with IC50 values ranging from 3.9 nM to 39.1 nM which remains in an excellent range of activity for all the compounds (Almabruk et al., 2013).

Figure 6

Antiplasmodial pactamycin analogues from Streptomyces.

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Table 6

 Antiplasmodial pactamycin analogues from Streptomyces.

Name

Strain, IC50

Source

Reference

56

Pactamycin

D6, 4.9 nM

Streptomyces pactum ATCC 27456

(Almabruk et al., 2013)

Dd2, 3.9 nM

7G8, 4.2 nM

57

TM-025

D6, 7.7 nM

Streptomyces pactum ATCC 27456

Dd2, 10.5 nM

7G8, 7.1 nM

58

TM-026

D6, 11.5 nM

Streptomyces pactum ATCC 27456

Dd2, 14.0 nM

7G8, 9.1 nM

59

TM-025F

D6, 12.3 nM

Synthetic

Dd2, 16.8 nM

7G8, 12.4 nM

60

TM-026F

D6, 26.5 nM

Synthetic

Dd2, 39.1 nM

7G8, 24.9 nM

Polyether compounds

From the literature accessed during our survey, three compounds described as polyethers have been isolated from Streptomyces sp. and described as demonstrating an antiplasmodial activity (Table 7, Figure 7). Abierixin (61) and its methylated derivative 29-O-methylabierixin (62) were isolated from Streptomyces sp. BCC72023 showed a moderate potency against P. falciparum K1 with IC50 values of 2.58 μg/ml and 1.40 μg/ml, respectively, while compound 63 isolated from Streptomyces sp. H668 was active against P. falciparum D6 and W2 with IC50 ranging from 100 to 200 ng/ml (Na et al., 2008; Supong et al., 2016).

Figure 7

Antiplasmodial polyethers from Streptomyces.

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Table 7

Antiplasmodial polyethers from Streptomyces.

Name

Strain, IC50

Source

Reference

61

abierixin

K1, 2.58 μg/ml

Streptomyces sp. BCC72023

(Supong et al., 2016)

62

29-O-methylabierixin

K1, 1.40 μg/ml

63

//

D6 and W2, 100 – 200 ng/ml

Streptomyces sp. H668

(Na et al., 2008)

Diketopiperazines

Two diketopiperazines (64 and 65) and one dimeric diketopiperazine (66) have been reported as antiplasmodial agents from Streptomyces strains (Table 8, Figure 8). Thus, the chemical investigations of the isolate S1 of Streptomyces sp. led to the isolation of piperafizine A (64) demonstrating activity of IC50 equal to 6.57 μM against P. falciparum Dd2 (Rakotondraibe et al., 2015), whereas another diketopiperazine identified as L-Pro-L-Leu (65) was obtained from Streptomyces sp. USC-16018 with 45.9 % inhibition of P. falciparum 3D7 and 39.0 % inhibition of P. falciparum Dd2 at 40 μM (Buedenbender et al., 2018). A dimeric analogue called naseseazine C (66) was reported in 2016 from the culture of Streptomyces sp. and was moderately active against P. falciparum 3D7 with an IC50 of 3.52 μM (Buedenbender et al., 2016).

Figure 8

Antiplasmodial diketopiperazines from Streptomyces.

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Table 8

Antiplasmodial diketopiperazines from Streptomyces.

Name

Strain, IC50

Source

Reference

64

Piperafizine A

Dd2, 6.57 μM

Streptomyces isolate S.1

(Rakotondraibe et al., 2015)

65

L-Pro-L-Leu

3D7, 45.9 % Inhib. at 40 μM

Streptomyces sp. USC-16018

(Buedenbender et al., 2018)

Dd2, 39.0 % Inhib. at 40 μM

6

Naseseazine C

3D7, 3.52 μM

Streptomyces sp.

(Buedenbender et al., 2016)

Miscelleaneous

Several other specialised metabolites from Streptomyces have been identified as antiplasmodial principles (Table 9, Figure 9). Among them, farneside A (67) was reported as a sesquiterpenoid nucleoside ether from Streptomyces sp. CNT-372 with moderate activity (IC50 of 69.3 μM) against P. falciparum 3D7 while 2-methylthio-N7-methyl-cis-zeatin (68), the first N7-methylated zeatin-type natural product has been reported from Streptomyces sp. 80H647 with a GI50 of 2.4 μM against the same parasite (Ilan et al., 2013; Lopez, Nogawa, Yosida, Futamura, & Osada, 2000). One polyenoic acid amide natural product named annimycin B (69) and a metabolite containing a γ-butyrolactone and 2-hydroxy-3-formylaminobenzoic acid moieties called opantimycin A (70) showed weak activity with 30% inhibition of P. falciparum Dd2, HB3, 3D7 at 2.5 μM; and IC50 of 13 μg/ml against P. falciparum 3D7, respectively (Zhang et al. 2014; ) (Nogawa et al., 2017).

Figure 9

Other antiplasmodial compounds from Streptomyces.

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Table 9

Other antiplasmodial compounds from Streptomyces.

Name

Strain, IC50

Source

Reference

67

Farneside A

3D7, 69.3 μM

Streptomyces sp. CNT-372

(Ilan et al., 2013)

68

2-Methylthio-N7-methyl-cis-zeatin

3D7, GI50 2.4 μM

Streptomyces sp. 80H647

(Lopez et al., 2000)

69

Annimycin B

Dd2, HB3 and 3D7, 30% of inhib. at 2.5 μM

S. asterosporus DSM 41452

(Zhang et al., 2018)

70

Opantimycin A

3D7, 13 μg/ml

Streptomyces sp. RK88-1355

(Nogawa et al., 2017)

71

Frenolicin B

HB3, 600 nM

Streptomyces roseofulvus

(Fitzgerald et al., 2011)

Dd2, 800 nM

7G8, 800 nM

72

Carbazomycin B

K1, 2.37 μg/ml

Streptomyces sp. BCC26924

(Intaraudom et al., 2011)

73

Carbazomycin C

K1, 2.10 μg/ml

74

Metacycloprodigiosin

K1, 0.0050 μg/ml

S. spectabilis BCC 4785

(Isaka et al., 2002)

75

Spectinabilin

K1, 7.8 μg/ml

76

Nocardamine

K1, 3.20 μg/ml

Streptomyces sp.BCC71188

(Supong et al., 2016)

77

Dehydroxynocardamine

K1, 2.63 μg/ml

78

Cyclooctatin

K1, 7.14 μg/ml

One benzoisochromanequinone frenolicin B (71) obtained from Streptomyces roseofulvus displayed good antiplasmodial activity against P. falciparum HB3, Dd2 and 7G8 with IC50 values of 600 nM, 800 nM and 800 nM, respectively (Fitzgerald et al., 2011). Similarly, the carbazole antibiotics named carbazomycins B (72) and C (73) were obtained from Streptomyces sp. BCC27095, as well as the tripyrrole pigment metacycloprodigiosin (74) and the nitrophenyl-substituted polyketide spectinabilin (75) from Streptomyces spectabilis BCC4785, were all evaluated against P. falciparum K1 and only compound 74 gave a strong activity with IC50 of 0.0050 μg/ml while compounds 72 and 73 gave a moderate activity with IC50 values of 2.37 μg/ml and 2.10 μg/ml, respectively; and finally, compound 75 was the less active with an IC50 of 7.8 μg/ml (Intaraudom et al., 2011; Isaka et al., 2002).

Two cyclopeptides namely nocardamine (76) and its derivative dehydroxynocardamine (77) have been isolated and characterized from Streptomyces sp. BCC71188. Both compounds were tested against P. falciparum K1 and found to be moderately active with IC50 values of 3.20 μg/ml and 2.63 μg/ml, respectively (Supong et al., 2016). Finally, the diterpenoid cyclooctatin (78) was obtained from the chemical investigations of Streptomyces sp. BCC71188 gave a moderate activity with an IC50 of 7.14 μg/ml against P. falciparum K1 (Supong et al., 2016).

Conclusion and future prospects

The data provided by the literature on the antiplasmodial compounds from Streptomyces support that these bacteria represent important sources of bioactive metabolites that can be considered as interesting candidates for new drugs discovery. In addition to be well reported as antibiotics, many Streptomyces-derived compounds demonstrated strong activities and were in some cases more effective than the reference drugs. For instance, three compounds including the macrolide munumbucin D and the two octadepsipeptides octaminomycins A (42) and B (43) displayed good antiplasmodial activity and did not show any cytotoxicity against several cell lines that increases their pharmacological interest for new drug development. Additional close checking indicated that several other compounds from Streptomyces have displayed strong or good potency against the drug-resistant strain K1 of P. falciparum. Among them, bafilomycin A1 (9), concanamycin A (10), elaiophylin (17), cyclomarin C (23), urdamycinone E (44), geldanamycin (52) and metacycloprodigiosin (74) demonstrated strong antiplasmodial with IC50 values of 0.041 μg/ml, 0.2 nM, 0.22 μg/ml, 0.24 μg/ml, 0.0534 μg/ml, 0.35 μg/ml and 0.0050 μg/ml, respectively, against P. falciparum K1. Inded, the discovery of a new compound with high potency against a chloroquine-resistant strain of P. falciparum like K1 or Dd2 might be a good starting point to address the problem of resistance of P. falciparum to prescribed drugs which is one of the most important factors to control in the eradication of malaria. Overall, despite the interesting in vitro antiplasmodial activity recorded so far for the indicated compounds, further in vivo, pharmacokinetic or ADMET studies are necessary to obtain more insights on their action mechanism, solubility or toxicity which are important to manufacturing a drug.

Conflicts of interest

The authors have no relevant financial or non-financial interests to disclose.

Author contributions

G.M.H : Conceptualization, Formal analysis, Methodology, Resources, Validation, Writing – original draft, Writing – review & editing. V.K.N : Data curation, Investigation, Structures drawing. D.S : Data curation, Investigation, Formal analysis. J.D.W : Conceptualization, Funding acquisition, Formal analysis, Methodology, Supervision, Project administration, Resources, Validation, Writing – review & editing