Use of elicitors to enhance or activate the antibiotic production in streptomyces

Figures & data

Figure 1. The elicitors DMSO and ethanol and their regulation of antibiotic production in Streptomyces. DMSO and ethanol are effective elicitors of secondary metabolism in Streptomyces and exert their effects by changing the membrane structure, affecting steady-state growth, and regulating associated genes and carbon metabolism. A-CoA: acetyl-CoA; Am-CoA: allylmalonyl-CoA; CIT: citrate; FK506: tacrolimus; DMSO: dimethyl sulfoxide; FK520: ascomycin; Glu-6-P: glucose 6-phosphate; HK-RR: histidine kinase–response regulator; Ile: isoleucine; M-CoA: malonyl-CoA; MET: methionine; MM-CoA: methylmalonyl-CoA; MOM-CoA: methoxymalonyl-CoA; OAA: oxaloacetate; P-CoA: propionyl-CoA; PEP: phosphoenolpyruvic acid; SP: sedoheptulose 7-phosphate; SUCC: succinic acid; TCA: tricarboxylic acid; Val-A: validamycin A; 1,3-DPG: 1,3-bisphosphoglyceric acid.

Figure 2. Enzymes and enzyme inhibitors can act as elicitors to activate or enhance antibiotic production in Streptomyces. ACP: acyl carrier protein; AT: acyltransferase; DH: β-hydroxyacyl-thioester dehydratase; KR: β-ketoacyl-ACP reductase; KS: β-ketoacyl-ACP synthase.

Figure 3. pH shock regulation in Streptomyces. Temperature shifts cause changes in antibiotic metabolism by influencing the TCA cycle, energy metabolism, and TCS. ACT: actinorhodin; CoQ: coenzyme Q; Cyt: cytochrome; Fe-S: iron–sulfur protein; FP: flavin proteases; P: phosphate group; TCA: tricarboxylic acid cycle; ε-PL: ε-poly-l-lysine; TCS: two-component regulatory system.

Table 1. Influence of rare earth elements (REEs) on antibiotic production.

REEs	Streptomyces	Functions	REE concentrations	Maximum multiple	Mechanisms	Ref
Sc	S. coelicolor	ACT overproduction	10–100 μM	Enhanced 25.3-fold at 30 μM Sc	Upregulated actII-ORF4, reduced the level of ppGpp	[37]
	S. parvulus	ACT overproduction	20–100 μM	Enhanced 2-fold	Unclarified
	S. lividans	ACT overproduction	20–200 μM	Enhanced more than 4.13-fold at 30 μM Sc	Up-regulation of actII-ORF4	[37]
	S. antibioticus	ACT activation	50–300 μM	More than 2-fold	Unclarified	[37]
	S. griseus	Streptomycin overproduction	10–200 μM	Enhanced 4-fold	A secondary effect of growth inhibition	[37]
	S.diastatochromogenes SD3145	Toyocamycin overproduction	5–20 μM	Enhanced by 1.4-fold	Unclarified	[38]
	S. coelicolor A3 (2) strain 1147	ACT overproduction	100–500 μM		Regulation of actIIORF4/ (redD) and other secondary metabolite biosynthetic genes	[36]
La	S. coelicolor A3 (2) strain 1147	ACT overproduction	1700–2500 μM		Regulation of actIIORF4 and other secondary metabolite biosynthetic genes	[36]
Others	S. coelicolor A3 (2) strain 1147	Enhanced ACT production	4 mg/ GYM agar		/	[36]

Sc: scandium; La: lanthanum; / : not mentioned; others: yttrium, cerium, praseodymium, neodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium; ACT, actinorhodin.

Table 2. Influence of nanoparticles on antibiotic production.

Nanoparticles	Nanoparticle concentrations	Streptomyces	Functions	Mechanisms	Ref.
CuO nanoparticle	10 mg/L CuO NPs (40 nm)	S. coelicolor	Enhanced actinorhodin by 2-fold	Increased ROS (approximately 2-fold) and glucose uptake by 133.9%; Upregulated genes involved in the ACT cluster and increased acetyl-coA production	[63]
CuO nanoparticle	5 mg/L CuO NPs (40 nm)	S. coelicolor	Enhanced actinorhodin approximately 1.8-fold	/	[63]
CuO nanoparticle	10 mg/L CuO NPs (80 nm)	S. coelicolor	Enhanced actinorhodin approximately 1.9-fold	Increased ROS and acceleration of glucose uptake to improve acetyl-coA production	[63]
CuO nanoparticle	10 mg/L CuO NPs (100 nm)	S. coelicolor	Enhanced actinorhodin approximately 1.8-fold	Increased ROS and acceleration of glucose uptake to improve acetyl-coA production	[63]
CuO nanoparticle	20 mg/L CuO NPs (40 nm)	S. coelicolor	Decreased actinorhodin by 0.76-fold	/	[63]
CuO nanoparticle	50 mg/L CuO NPs (40 nm)	S. coelicolor	Decreased actinorhodin by 0.76-fold	/	[63]
CuO nanoparticle	100 mg/L CuO NPs (40 nm)	S. coelicolor	Decreased actinorhodin by 0.76-fold	/	[63]
Al2O3 nanoparticle	1000 mg/L Al2O3 NPs (80 nm)	S. coelicolor	Enhanced undecylprodigiosin by 3.7 fold	Increased expression levels of antibiotic biosynthetic genes and two-component systems (TCSs); inhibited expression levels of primary metabolic pathways	[64]
Al2O3 nanoparticle	1000 mg/L Al2O3 NPs (80 nm)	S. coelicolor	Enhanced actinorhodin by 4.6 fold and produced approximately 24 h earlier	Increased expression levels of antibiotic biosynthetic genes and two-component systems (TCSs); Inhibited expression levels of primary metabolic pathways	[64]
Ball-milled biochar	10 mg/L	S. coelicolor	Produced RED 4 h earlier and increased yield by 3.2-fold	Increased expression of pathway-specific regulatory genes redD, redZ and actII-ORF4	[65]
Ball-milled biochar	10 mg/L (10–1000 nm)	S. coelicolor	Produced ACT approximately 24 h earlier and increased production by 2.9-fold	Increased expression of pathway-specific regulatory genes redD, redZ and actII-ORF4	[65]
Graphene oxide	10 mg/L (0.5–3 μm)	S. coelicolor	Improved ACT by 1.7-fold	Increased expression of pathway-specific regulatory genes redD, redZ and actII-ORF4	[65]
Ball-milled biochar	1 mg/L (0.5–3 μm and 10–20 nm)	S. coelicolor	Improved ACT by 1.7-fold	Increased expression of pathway-specific regulatory genes redD, redZ and actII-ORF4	[65]

/: not mentioned; ROS: reactive oxygen species; ACT: actinorhodin.

Table 3. Influence of co-culture on antibiotic production.

Acceptors	Donors	Donor character	Functions	Ref.
S. clavuligerus	S. aureus N315		Holomycin induced	[140, 142]
S. coelicolor	S. griseus	Streptomyces	Enhanced ACT	[141]
S. coelicolor	S. erythraea		Enhanced ACT	[141]
S. lividans	T. pulmonis	Mycolic acid-containing bacteria	ACT and RED induced	[142]
S. lividans	C. glutamicum	Mycolic acid-containing bacteria	RED induced	[142]
S. endus S522	T. pulmonis	Mycolic acid-containing bacteria	Alchivemycin A and B induced	[142]
S. cinnamoneus NBRC 13823	T. pulmonis	Mycolic acid-containing bacteria	Arcyriaflavin E induced	[143]
Streptomyces sp. CJ-5	T. pulmonis	Mycolic acid-containing bacteria	Chojalactone induced	[144]
Streptomyces sp. NZ-6	T. pulmonis	Mycolic acid-containing bacteria	Niizalactam induced	[144]
S. nigrescens HEK616	T. pulmonis	Mycolic acid-containing bacteria	5-Alkyl-1,2,3,4-tetrahydroquinolines induced	[145,146]

ACT: actinorhodin; RED: undecylprodigiosin.

Figure 4. Complex communities induce unnatural antibiotic production. Fungal cell fragments, substances involved in interactions, and physical contact with Streptomyces species can enhance antibiotic biosynthesis.

Figure 5. ROS influence secondary metabolism as intercellular and intracellular signals. ROS may act as intercommunal and intracellular signals to mediate secondary metabolism in Streptomyces. ACT: actinorhodin; CA: clavulanic acid; DXR: doxorubicin; God: goadsporin; ROS: reactive oxygen species; Val-A: validamycin A; ε-PL: ε-poly-l-lysine.

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