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.

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 & Wilairat, 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 (25‒41) with significant potencies have been prepared from desoxycyclomarin C (24).

Figure 3

Antiplasmodial polypeptides from Streptomyces.

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 (25‒41) 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

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.

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.

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.

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.

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.

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).