Microbial symbionts of insects as a source of new antimicrobials: a review

Figures & data

Figure 1. Graphical overview of the five main steps in the screening methodology of antimicrobial- producing insect symbionts. A popular method of identifying active insect symbionts and metabolites relies on microbial isolation and culturing, before performing an antimicrobial screening. In this traditional screening methodology, various key steps can be identified, indicated by the fields in various colours: isolation of insect symbionts, identification of isolates, fermentation and extraction, antimicrobial screening, and finally structure elucidation of active compounds. There is no fixed order when performing these steps, as indicated by the arrows.

Figure 2. Orders and genera of insects of which microbiota are investigated for antimicrobial activity. The inner-circle represents the orders of the insects, the outer circle represents the insects’ genera.

Figure 3. A graphical overview of the orders and genera of the insect symbionts with reported antimicrobial activity. Graph a shows the symbionts that have been found active through broad screening studies. Graph b shows active insect microbes that have been selected as symbiont of interest prior to antimicrobial screening. Graphs present microbes on genus level, and multiple species within the same genus were counted as one.

Figure 4. Overview of compounds with antimicrobial activity from insect symbionts. a) Amount of studies that isolated secondary metabolites from the symbiont(s) of interest. b) Visual representation of the structural classes the active molecules belong to.

Table 1. Overview of compounds with antimicrobial activity isolated from insect symbiont strains.

Structural classification	Compound	Symbiont strain	Insect origin	Activity against	Strength of activity	MIC in µM^b	References
Peptides
Lipopeptide	Stephensiolides A–K	S. marcescens	A. stephensi	- B. subtilis - P. falciparum	IC50 of 15 µg mL^−1IC50 of 14 µg mL^−1		Wu et al. (2014)
Polyketide-peptide	Dentigerumycin	Pseudonocardia sp.	A. dentigerum	- Escovopsis sp. - C. albicans	MIC of 2.8 µMMIC of 1.1 µM		Mandal et al. (2013), Vivero et al. (2019)
	Boydine B	P. boydii	H. parallela	- Bifidobacterium sp.- Veillonella parvula - Anaerostreptococcus sp.- Bacteroides vulgatus - Peptostreptococcus sp.	MIC of 0.2 µMMIC of 0.2 µMMIC of 0.2 µMMIC of 0.8 µMMIC of 0.2 µM		Correa et al. (2019)
Poly-ketides
Polycylic polyketide	Fasamycin C-E	S. formicae	T. penzigi	- B. subtilis - MRSA - VRE	MIC <2.5–10 µM^aMIC 0.625–20 µM^aMIC 1.25–80 µM^a		Raaijmakers et al. (2010)
	Formicamycins A-M	S. formicae	T. penzigi	- B. subtilis - MRSA - VRE	MIC <20–5 µM^aMIC 10–80 µM^aMIC 10–80 µM^a		Raaijmakers et al. (2010)
Macrocyclic, macrolide	Cyphomycin	Streptomyces sp.	Cyphomyrmex sp.	- Escovopsis sp. - C. albicans - C. glabrata - C. auris - A. fumigatus	Not mentionedMIC of 0.25 µg mL^−1MIC of 0.5 µg mL^−1MIC of 4 µg mL^−1 MIC of 0.5 µg mL^−1	0.17 µM0.34 µM2.74 µM0.34 µM	Van Arnam et al. (2018)
Macrocyclic, macrolactam	Frontalamide A and B	Streptomyces sp.	D. frontalis	- O. minus	Not mentioned		Abriouel et al. (2011)
	Natalamycin A	Streptomyces sp.	M. natalensis	- Pseudoxylaria sp.- Termitomyces sp.	Not mentionedNot mentioned		Moraes et al. (2014)
Macrocyclic, polyene	Selvamicin	Pseudonocardia sp.	Apterostigma sp.	- C. albicans - S. cerevisiae - A. fumigatus - T. harzianum	MIC of 23 µM“similar activity”“similar activity”“similar activity”		Poulsen et al. (2011)
	Sceliphrolactam	Streptomyces sp.	S. caementarium	- C. albicans	MIC of 4 µg mL^−1	8.31 µM	Madden et al. (2013), Chalasani et al. (2015)
Non-macrocyclic, non-polycyclic	Lagriamide	B. gladioli	L. villosa	- P. lilacinum	12 mm inhibition zone		Kikuchi (2009)
	Mycangimycin	Streptomyces sp.	D. frontalis	- O. minus - C. albicans - S. cerevisiae - Penicillium sp. - P. falciparum	MIC of 1.2 µg mL^−1MIC of 0.2 µg mL^−1MIC of 0.4 µg mL^−1MIC of 6.2 µg mL^−1EC50 of 17 ng mL^−1	3.65 µM0.61 µM1.22 µM18.88 µM0.052 µM	Akbar et al. (2018), Toledo et al. (2015)
	Ilicicolinic acid C	N. discophora	N. corniger	- E. coli - T. rubrum - C. albicans	MIC of 8 μg mL^−1MIC of 4 μg mL^−1MIC of 32 μg mL^−1	19.91 µM9.46 µM75.65 µM	Matarrita-Carranza et al. (2017)
	Ilicicolinic acid D	N. discophora	N. corniger	- E. coli - T. rubrum - C. albicans	MIC of 8 μg mL^−1MIC of 32 μg mL^−1MIC of 16 μg mL^−1	19.91 µM9.46 µM75.65 µM	Matarrita-Carranza et al. (2017)
	N-methyltyroscherin	P. boydi	Nasutitermes	- C. albicans - T. rubrum	MIC of 4 μg mL^−1MIC of 4 μg mL^−1	11.51 µM11.51 µM	Oh et al. (2009)

All included molecules were at the time of their discovery in the insect symbiont not yet described elsewhere. Activity is usually expressed as the concentration needed for 50% growth inhibition (IC50), and sometimes the lowest concentration at which no growth is seen (minimal inhibitory concentration, MIC).

MRSA: methicillin-resistant S.aureus; VRE: vancomycin-resistant Enterococcus faecium

^aActivity is given as a range for a large group of molecules.

^bFor single, purified compounds, minimal inhibitory concentrations that are originally expressed in μg mL⁻¹ are converted to values in µM to facilitate comparison of activity.

Figure 5.1. Molecular structures of new active peptides found in insect symbionts. (a) The cyclic lipodepsipeptide stephensiolide H. (b) Dentigerumycin, a polyketide-peptide hybrid. The polyketide fragment is indicated in red (c) The fungal toxin Boydine B, an epipolythiodioxopiperazine derived from a cyclic peptide.

Figure 5.2. Molecular structures of new active polyketides found in insect symbionts. (d) Formicamycin F, one of the new pentacyclic polyketides. (e) Cyphomycin, a macrolide polyketide. (f) Frontalamide B, a polyketide with a macrolactam structure. (g) Natalamycin, a macrolactam polyketide. The substituted phenol function that replaces the benzoquinone function of the geldanamycins, is indicated in red. (h) Selvamicin, a polyene macrolide structurally very similar to the polyene antibiotics nystatin and amphotericin B. Indicated in red, is the sugar function that substitutes the amino sugar group of the regular polyene antibiotics. (i) Sceliphrolactam, a macrocyclic polyene. (j) Mycangimycin, a polyene peroxide with no macrocyclic ring structure. (k) Lagriamide, a polyether polyketide. (l) Ilicicolinic acid C. The carboxylic acid function is indicated in red. (m) N-methyltyroscherin, another non-polycyclic polyketide.

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