Summary of masseter toxin injection complications.
\r\n\tFrom a public health perspective, reduced health literacy can lead to widespread consequences. “Low health literacy is also costly for the country because when people don't understand health information and instructions, they are more likely to have worse health outcomes and unnecessarily use emergency room services,”. Experts agree that health literacy is vital to reducing healthcare costs and improving public health. The path to improving health literacy isn’t always straightforward, however.
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\r\n\t“Unfortunately, up to 9 out of 10 adults can have limited health literacy, and this can be fluid,” Blue says. “It can be more challenging to be health literate when we are sick or in pain, so even someone who normally has a high level of health literacy may struggle at times to understand and process health information.”
Global consensus on facial beauty in different races shares certain common features, including an oval facial shape and a V-shaped chin and jawline [1, 2]. One of the characteristic features of an Asian face is a square-shaped lower face caused by masseter muscle hypertrophy, making this a popular request for esthetic treatment [3, 4, 5, 6, 7]. Since the first report on treating masseter hypertrophy with botulinum neurotoxin (BoNT) was published in 1994 [8], BoNT injections for masseter hypertrophy have become quite popular not just among Asian patients but among Caucasian patients as well [9, 10], despite being an off-label indication.
Generally, the treatment of masseter muscle hypertrophy with BoNT-A is very effective and quite safe, though the possibilities of side effects still exist and are prevalent enough to warrant attention [3, 5, 7, 9, 10, 11, 12]. Recently, our group reported the collective data on 680 masseter hypertrophy patients receiving 2036 BoNT-A treatments over a 6-year period [13]. The causes of side effects after masseter toxin injection treatment were organized into four groups and summarized in Table 1. Each complication will be discussed separately below.
Category | Etiology/cause | Prevention/treatment | Incidence |
---|---|---|---|
Nonmuscular origin | |||
Bruising | Damaged vessels | Compression after inj. | 2.5% [13] |
Hematoma (rare) | Trauma to the arteriole or vein | Compression after inj. | N/A |
Dizziness | Unknown | Rest | 0.9% [12] |
Headache | Unknown | Rest | 0.58% [13] |
Toxin effect-related | |||
Chewing weakness | Transient muscle weakness | Abates within a week | 30% [13] |
Temporalis m. hypertrophy | Compensatory m. overactivity | Injection over temporalis m. | N/A |
Dosage-level-related | |||
Poor or no effect | Insufficient dosage/overly superficial inj. | Good inj. Dose/depth/toxin resistance | No effect (0.1%) [13] |
Asymmetricity | Same dose on different sizes of hypertrophy m. | Adjust dose according to muscular size | N/A |
Jowling/sagging | High dosage in elderly patient | Reduce dose, multiple ℞, inj. lower face depressors (platysma) | 0.20% [13] |
Paradoxical bulging (muscle bulging during mastication) | Superficial masseter m. fiber overactivity | Inj. over superficial masseter if not abated after 1–2 weeks Prevent inj. deep and superficial m. fibers | 0.49% [13] |
Injection site-related | |||
Sunken temporal fossa | Atrophy of the temporalis m. and downward displacement of the temporal and cheek fat pads | Prevent inj. too high Filler injection over temporal area | 0.05% [14] |
Loss of full smile/asymmetric smile | Inj. too high or anterior, effect on zygomatic major or risorius m. | Inj. in the injection safe zone, and ideally keep 0.5–1 cm from each border of the safe zone Most complications resolve spontaneously after some time | 0.15% [13] |
Sunken lateral cheeks (infrazygomatic hollow) | Inj. too high, excess dose | 0.44% [13] | |
Difficulty in mouth opening | Inj. too high, effect on lateral pterygoid m. | 0.9% [12] | |
Xerostomia | Inj. too posterior, effect on parotid gland function | 6.3% [14] | |
Neuropraxia (very rare) | Inj. too inferior, damage to marginal mandibular nerve | One case report [15] |
Summary of masseter toxin injection complications.
This includes bruising, hematoma, headaches, and dizziness.
Injury of small vessels during injection may cause bruising. Bruising is one of the most common but least severe side effects and usually dissipates in 5–7 days without sequelae. Our study reported a bruising incidence rate of 2.5%.
The masseter muscle is a relatively thick and strong muscle and is well vascularized. There are four major arteries that supply the upper, middle, lower, and medial parts of the masseter: the external carotid artery, the facial artery, the maxillary artery, and branches of the superficial temporal artery [16]. Needle penetration of these arteries and subsequent failure to apply compression may result in hematomas.
Headaches after treatment is of unknown etiology and is also quite rare, with literature usually reporting below 1% (our study reported 0.58%). It may be linked to individual physiological differences, and the same individuals who have suffered from posttreatment headaches are likely to encounter headaches again in the future treatment. Headaches may occur immediately after injection and take about 2–4 days to recover.
This includes chewing weakness and temporalis muscle compensatory hypertrophy.
Decreased masticatory force is the most commonly encountered side effect of masseter toxin injection: our study reported a prevalence of 30%. This side effect is caused by BoNT physiology and is perhaps unavoidable in cases where higher dosages are required. Reduction of mastication force starts at around 1–4 weeks after treatment and gradually improves in the following weeks. Mastication force generally returns to pretreatment levels by the 12th week of postinjection [17, 18].
Since chewing weakness is the most commonly encountered side effect, it is theoretically possible, though not yet reported, for patients to develop compensatory overactivity and hypertrophy of another mastication muscle such as the temporalis muscle.
This includes poor effect, asymmetricality, jowling, sagging, and paradoxical bulging.
Poor effect of treatment is mostly due to insufficient dosage or a superficial placement of the toxin. However, it is also possible (though extremely rare; only one case was reported by our study) for a patient to exhibit a complete lack of response to treatment. The etiology of this may be due to individual immunity to the toxin.
Asymmetry may occur if the physician fails to recognize the size differences between the left and right masseters before treatment. In many patients, unilateral preference in chewing will result in a bilateral discrepancy in masseter size. It is crucial to keep this in mind when doing pretreatment evaluations, which then allows the physician to adjust the dosage according to the patient’s underlying asymmetry.
Worsened jowls is likely due to overly rapid posttreatment masseter atrophy, which results in volume reduction and sagging of the overlying soft tissue envelope [9]. The incidence of this complication is around 0.2% as reported by our study and usually occurs in patients over 40. To prevent this side effect, physicians should reduce the dose and separate treatment into multiple sessions, which will slow down the speed of muscular atrophy and provide enough time for the overlying skin to contract. Additional toxin injection into the platysma muscle may mitigate facial depressor action, making sagging less likely.
Paradoxical bulging, or masseter bulging during mastication [19], has an incidence rate around 0.49% as reported by our study. Excessive compensation of the untreated superficial layer of the masseter muscle may be a possible explanation for this complication. A recent published study [20] discovered a tendinous structure (deep inferior tendon (DIT)) located in the deeper part of the superficial masseter muscle layer in all cadaver specimens examined. The DIT may block toxin diffusion from the deep layer to the superficial layer; therefore, the superficial layer may be unaffected and prone to overcompensation in the event of masseter weakness [20]. The onset of paradoxical bulging is usually within 24 hours of treatment, and recovery is within 10 days [9]. If recovery has not been achieved within 10–14 days, a booster BoNT injection of about 5–10 units to the untreated superficial layer can usually correct this side effect. Injecting both deep and superficial muscle fibers should prevent this side effect [20].
This includes the loss of the full smile, asymmetrical smile, sunken lateral cheeks, difficulty in opening of the mouth, xerostomia, and neuropraxia.
Also called smile limitation, our study reported incidence rates of about 0.15%. Smile limitation may be due to toxin diffusion into the risorius muscle; in a cadaver study, the risorius attaches to the anterior or middle part of the masseter in more than 97% of cases [21]. Smile limitation usually takes around 1–3 months to recover [9]. Thorough knowledge of muscular anatomy is important to prevent this complication, and the physician should set an injection safe zone at least 1 cm from the anterior border of the masseter and keep to a deep injection level.
An asymmetric smile may be caused by paralysis of the zygomatic major muscle. This may occur if the physician injects in a position which is too high and too anterior. Keep the injections to the lower, more posterior part of the masseter muscle to avoid this complication.
The sunken lateral cheek, or concave below the zygomatic arch, is caused by over hollowing of the infrazygomatic region resulting from volume loss over the upper parts of the masseter muscle. Our study reports an incidence rate of about 0.44%. Sunken lateral cheeks may be due to a high position of injection and simply keep the injection sites over the lower part of the masseter to prevent it.
Difficulty in opening of the mouth is a rare complication; according to one report, the incidence was 2 out of 220 treated patients [12]. This complication is caused by toxin paralysis of the lateral pterygoid muscles, possibly arising from an injection site that is high and deep enough to reach past the coronoid notch and affect the pterygoid muscle. Another possible etiology may be abnormal activity of the temporomandibular joint. For prevention, the physician should only inject the lower part of masseter muscle and keep at least a centimeter below the upper safety margin of masseter injection.
Sunken temporal fossa is a rare side effect with an incidence of about 0.05%, as reported by a Chinese study in 2017 [22]. This complication is likely from a combination of two etiologies: atrophy of the temporalis muscle as a result of drug dispersion and downward displacement of the temporal and cheek fat pads as a result of masseter relaxation [22]. This side effect appears about 1 month after treatment.
Xerostomia is a complication due to toxin effect on the parotid gland. The reported incidence rate for xerostomia is around 6.3% [14]. Keeping the injection site 1 cm away from the posterior margin of the masseter (thus avoiding the usual location of the parotid gland) can be helpful for the prevention of xerostomia.
Neuropraxia [11] is a very rare complication caused by paralysis of the marginal mandibular nerve. There has only been one case report in which the patient experienced temporary marginal mandibular nerve paralysis. Symptoms improved within 2 weeks [15].
In one cadaver study, the marginal mandibular nerve runs about 0.1–1.0 cm from the mandibular border [23]. Physicians should therefore keep the injection site 1 cm from the lower margin of the masseter.
Neurapraxia is an exceedingly rare complication and is caused by paralysis of the marginal mandibular nerve. There were no cases in the author’s two decades of experience with masseter toxin injections.
A range of other possible adverse effects may occur but are usually only reported in single case reports. These include speech disturbance, altered gustatory sensation, incidental aggravation of venous malformation, madarosis, facial alopecia, and acute visual loss [4, 5, 6, 24, 25, 26, 27].
If the anterior to posterior width of the masseter is less than 3–5 cm, inject 20–30 units of onabotulinum toxin per side [28]. This amount may vary slightly by case depending on muscle size and individual needs. Repeated injection could be done every 3–6 months for optimized cosmetic outcome.
Before injection, physician should mark the anterior, posterior, inferior, and superior borders of the “injection safe zone.” The anterior and posterior borders of the safe zone are the anterior and posterior edges of the masseter muscle, and the inferior border is the inferior edge of the mandible. The upper border of safe zone runs from the mouth corner to the earlobe. Keep injections inside the safe zone and ideally in 3–4 different locations at least 0.5–1 cm from each border (Figure 1).
The recommended safety zone for masseter toxin injections is a quadrilateral with its upper border running from mouth corner to earlobe, its anterior and posterior borders the anterior and posterior edges of the masseter muscle, respectively, and its inferior border the inferior edge of the mandible. Injection safe zone, marked in lighter blue, and the ideal injection safe zone of 1cm away from each border, marked in darker blue. The mandible angle marked with large red circle. Suggested injection points mark with small red dot, with 3 points (A) or 4 points injection (B).
BoNT-A masseter injections can achieve satisfactory results with mostly mild and infrequent complications. However, adverse effects can still impact patient satisfaction, so an understanding of the regional muscular anatomy, appropriate dosing, injection location, and injection depth are all important aspects to consider when planning and performing treatment. In particular, the injection safety zone should be clearly demarcated by the physician before injection by identification of its four borders: upper border running from the mouth corner to the earlobe, anterior and posterior borders of the anterior and posterior edges of the masseter muscle, respectively, and inferior border of the inferior edge of the mandible. Keeping injections inside the safe zone, and ideally in 3–4 different locations at least 1 cm from any border, is crucial for the prevention of common side effects mentioned above (Figure 1A and B). Physicians should also know about the different characteristics of various complications, their etiological origin, their management, and their prevention.
Nothing to disclose for this report.
Secondary metabolites are biologically active small molecules that are not required for growth and development but which provide a competitive advantage to the producing organism [1]. These are small organic molecules that consist of unusual chemical structures which include β-lactam rings, cyclic peptides, depsipeptides containing unnatural and non-protein amino acids, unusual sugars and nucleosides, unsaturated bonds of polyacetylenes and polyenes, covalently bound chlorine and bromine; nitro-, hydroxamic acids, and so on. Their enormous diversity includes 22,000 terpenoids as well [2]. These complex molecules are commonly obtained from molds which make 17% of all antibiotics and actinomycetes make 74% [3]. The bacterial secondary metabolites are a source of many antibiotics, chemotherapeutic drugs, immune suppressants, and other medicines. Some species are relatively more prolific in secondary metabolism, for example, strains of
As microorganisms are rarely found in isolation, the presence of secondary metabolites in a microbial community exerts evolutionary pressure on both secondary metabolite-producing and non-producing members to develop means to withstand them. They either use secondary metabolites to have competitive advances or support the intra/interspecies communities against stressful environmental conditions. As these molecules play a vital role in the survival of various microbes, biosynthesis of these molecules is tightly regulated via various transcriptional factors which got triggered under stringent conditions.
This chapter is dedicated to the role of secondary metabolites as antibiotics by various species. The first section of the chapter begins with a discussion on how these molecules are utilized by the various organisms to ensure their survival in the environment. The second section of the chapter goes into the details of how secondary metabolites affect the metabolism of the organism and alter their own or other’s organism susceptibility against antibiotics. And the last section discusses how these secondary metabolites as antibiotics are regulated and synthesized with a special focus on
In recent years, the view that secondary metabolites facilitate the survival of the producer in competition with other living species has been expressed more widely [8, 9]. Some common arguments behind such a view are as follows: (1) Organisms that lack an immune system are prolific producers of these compounds which act as an alternative defense mechanism. (2) The compounds have sophisticated structures, mechanisms of action, and complex and energetically expensive pathways which can only exist if they provide survival advantage to the organism [10]. (3) They are produced in nature and used in competition between microorganisms, plants, and animals [11, 12]. (4) Biosynthetic genes of secondary metabolites are clustered, which would only be selected for if the product conferred a selective advantage, and the absence of non-functional genes in these clusters. (5) The presence of resistance and regulatory genes in these clusters, and lastly by not least the non-producers have clustering of resistance genes.
Besides providing a survival advantage to microbes, secondary metabolites with antibacterial and antifungal properties can cause public health problems if found in soil, straw, and agricultural products. These are usually considered to be mycotoxins, but they are nevertheless antibiotics. And the natural production of such toxic metabolites is one of our major public health problems in the field and during the storage of crops. Natural soil and wheat straw contain patulin [13] and aflatoxin is known to be produced on corn, cottonseed, peanuts, and tree nuts in the field [14]. These toxins can cause hepatotoxicity, teratogenicity, immunotoxicity, mutation, cancer, and death [15].
Below list provide some of the functions of secondary metabolites with examples found across various species from single cell microbes to multicellular organisms.
Agents of chemical warfare in nature
According to Cavalier-Smith [16], secondary metabolites are most useful to the organisms producing them as competitive weapons. Antibiotics are more effective than macromolecular toxins such as animal venoms because of their higher diffusibility into cells and broader modes of action and diverse molecular structure varieties possible.
Microbe vs. microbe:
In nature, competition between various fungi has been demonstrated in virtually every type of fungal ecosystem including coprophilous, carbinocolous, lignicolous, fungicolous, phylloplane, rhizosphere, marine, and aquatic [17].
Bacteria produce antibiotics when they need them for survival. For instance, myxobacteria can grow on
Bacteria vs. amoebae:
As eukaryotes cells such as amoebae, a protozoans cell, feed on bacteria [19], bacteria found their ways to protect themselves against amoebae and other protozoans in general. Both
Microorganisms vs. higher plants:
Over 150 microbial compounds called phytotoxins have been reported that are active against plants [20]. Several such phytotoxins (e.g., phaseolotoxin, rhizobitoxine, and syringomycin) show typical antibiotic activity against other microorganisms and are thus belong to a class of antibiotics.
Plants produce antibiotics called phytoalexins after being exposed to plant pathogenic microorganisms in order to protect themselves [21]. They are of low molecular weight, weakly active, and indiscriminate, that is, they inhibit both prokaryotes and eucaryotes including higher plant cells and mammalian cells.
Microorganisms vs. insects:
Certain fungi produce secondary metabolites for entomopathogenic activity: infecting and killing insects.
Similarly, to fight back against bacterial infections, insects produce antibacterial proteins [24]. Some of these proteins are lysozyme, sarcotoxins, cecropins, and defensins. These proteins are either bactericidal or bacteriostatic by nature.
Microorganisms vs. higher animals:
It is beneficial for microbes to make fresh food as objectionable as possible to large organisms as quickly as possible [25]. They produce secondary metabolites such as antibiotics and toxins which are toxic to large animals such as livestock. Thus, large animals will refuse to consume moldy feed which ensures the availability of food sources for various microbes.
If in case, animals and plants do get infected from microbes, they produce various peptides which kill microbes by permeabilizing their cell membranes as a way to defend against microbial infection [26].
Metal transport agents
Certain secondary metabolites can act as metal transport agents. Siderophores (also known as sideramines) containing molecules function in the uptake, transport, and solubilization of iron. Siderophores are complex molecules that solubilize ferric ion which has a solubility of only 10−18 mol/L at pH 7.4 and have an extremely high affinity for iron (
Iron-transport factors in many cases are antibiotics by nature. They are on the borderline between primary and secondary metabolites since they are usually not required for growth but do stimulate growth under iron-deficient conditions. Antibiotic activity is due to the ability of these compounds to starve other species of iron when the latter lack the ability to take up the Fe-sideramine complex. Such antibiotics include nocardamin [27] and desferritriacetylfusigen [28].
Secondary metabolites can bring profound variation in microbial physiology, metabolism, and stress responses [29]. Several evidence suggest that these molecules can modulate microbial susceptibility to commonly used antibiotics. This section explores which types of secondary metabolites alter antimicrobial susceptibility, and how and why this phenomenon occurs.
In a given environment, microorganisms are rarely found in isolation. Due to such reasons, the presence of secondary metabolites in a microbial community exerts evolutionary pressure on both secondary metabolite-producing and non-producing members to develop means to withstand them. Generally, secondary metabolites alter the state of metabolism which directly has an impact on an organism’s ability to withstand antibiotics assault by either increasing its tolerance or making itself more resistant.
Although antibiotics tolerance and resistance are often treated in a similar manner, they offer different abilities to the microorganism. The phenomenon of antibiotic tolerance is the ability of organism to survive transient antibiotic exposure while resistance is the ability of organism to grow in the presence of antibiotics at a given concentration [30, 31, 32]. Another generic term commonly used is antibiotic resilience which refers to the ability of a bacterial population to be refractory to antibiotic treatment, which can arise from an increase in tolerance and/or resistance.
There are common modes of action through which secondary metabolites molecules can alter antibiotic efficacy in both single-species and polymicrobial communities. Specifically, secondary metabolites can regulate multidrug resistance efflux systems, can modulate the toxicity of antibiotics through interactions with reactive oxygen species (ROS) and can induce antibiotic tolerance to provide an overlooked route for the evolution of antibiotic resistance.
The knowledge of such interactions between secondary metabolites and antibiotic efficacy is beneficial as this could be applied to optimize the use of existing antimicrobial drugs and generate targets for novel therapeutic strategies.
One common mechanism bacteria use to tolerate clinical antibiotic treatment is by activation of efflux pumps that export toxins out of the cell [33, 34]. However, efflux pumps exist long before human use of synthetic antibiotics and therefore are presumed to have originally evolved to transport other, naturally occurring, substrates, such as secondary metabolites [35, 36]. Importantly, efflux pumps vary in their specificity, with regard to both their regulation and their substrate affinity [37]. Therefore, it is essential to understand how the secondary metabolite interacts with the transcriptional regulation of the efflux system, as well as which classes of drug the efflux system can transport before one predict whether a secondary metabolite will increase antibiotic resilience in its producer through the induction of a particular efflux system or not. A well-known example of a secondary metabolite that affects the efflux system is indole. Indole is a signaling molecule self-produced by
As mentioned earlier, efflux pumps are evolved to transport in general various molecules including secondary metabolites, efflux pumps can also provide protection against secondary metabolites that are toxic to their producers. For instance, phenazines are redox-active and toxic secondary metabolites produced by the
A related phenomenon has been observed in the Gram-positive bacterium
The idea of oxidative stress become well known when it was proposed that regardless of the specific cellular targets of various antibiotic classes, bactericidal antibiotics exert their lethal effects in part by inducing oxidative stress [48]. Although this hypothesis resulted in major controversies [49, 50], evidence reviewed elsewhere [51] suggests that bactericidal antibiotics do impact cellular redox states and that the resulting increase in ROS and oxidative stress can contribute to cell death. Such phenomena relate well with secondary metabolites as they also interface with cellular redox homeostasis and oxidative stress responses. Below three different modes of action are discussed by which secondary metabolites can potentially antagonize or potentiate the toxicity of antibiotics: upregulation of oxidative stress response genes; direct detoxification of ROS; and increased endogenous ROS generation.
Secondary metabolites that upregulate the expression of oxidative stress responses can prime bacterial cells for tolerance and/or resistance to antibiotics, which is similar to the protective effects of exposure to sublethal concentrations of oxidants such as H2O2 [52]. Among this class of metabolites, indole is a non-toxic molecule produced by
Another example of the secondary metabolite is pyocyanin (PYO) produced by
Another way to protect against antibiotic assaults of oxidative stress is by directly detoxifying antibiotic-induced ROS by upregulating the antioxidant activity. Ergothioneine, is one of two major sulfur-containing redox buffers in mycobacteria, along with mycothiol which help in detoxifying ROS during the stress response. This molecule is so important for the
So far secondary metabolites have been demonstrated to decrease antibiotic efficacy by attenuating oxidative stress. However, they can also amplify the toxicity of antibiotics by increasing ROS generation. 2-heptyl-3-hydroxy-4-quinolone is one example, also known as the
So far, we have discussed examples of how secondary metabolites affect their producers susceptibility to antibiotics. However, secondary metabolites can also modulate interspecies antibiotic resilience. Such study is beneficial as it will potentially show how interactions among members of a polymicrobial infection might affect antibiotic treatment outcomes [65, 66]. For example, one study has demonstrated that indole, which is produced by
Importantly, although the above examples suggest that certain secreted secondary metabolites have the potential to raise the community-wide level of antibiotic resilience in polymicrobial communities, it may not be this case always. As mentioned earlier that secondary metabolites can be toxic or non-toxic and can increase or decrease resilience against antibiotics, it is important to consider whether the stress caused by the secondary metabolite is tolerable to the non-producing species. If the molecule-caused toxicity outweighs the benefits it provides against antibiotics, the non-producing species would not gain a benefit. In such a case, the secondary metabolite might even act synergistically with the clinical antibiotic [69].
So far, we have discussed what different kinds of secondary metabolites exist, how they affect cellular metabolism and help in survival in competitive and stressful environments. This last section focuses on the factors on which the biosynthesis of secondary metabolites is regulated. This will show how different conditions lead to the secretion of secondary metabolites which leads to phenomena discussed in the previous two sections. As the exploration of regulation of secondary metabolites among various species is still in its early stages except for Streptomycetes, this section will focus on its regulatory mechanisms behind biosynthesis of secondary metabolites.
Streptomycetes and other actinobacteria are renowned as a rich source of natural products of clinical, agricultural, and biotechnological value. Sequencing genomes of numerous streptomycetes has revealed that they all possess the capacity to produce multiple secondary metabolites [70, 71] implies that it can repel a large number of competitors using either individual or combination of molecules using their synergistic characteristics [72]. The genes of enzymes responsible for the production of individual secondary metabolites are found clustered. Furthermore, these clustered genes are commonly associated with regulatory gene/s that regulate their transcription or resistance genes.
This section discusses some of the factors which regulate the production of secondary metabolites in
Generally, a single regulatory gene regulates several gene clusters associated with secondary metabolites production. This way multiple chemical signals which can trigger activation of the regulatory gene can activate specific or multiple genes clustered corresponding to secondary metabolite production. Some of the gene clustered include the clusters for streptomycin in
Stringent response is an stress response of bacteria in reaction to amino-acid starvation, fatty acid limitation, iron limitation, heat shock, and other stress conditions. During stringent response, accumulation of (p)ppGpp enables bacteria to survive sustained periods of nutrient deprivation. For several
The availability and source of carbon have a substantial effect on the production of antibiotics and morphological development [81]; for example, glucose blocks production of ACT by
Numerous studies have shown that the source of nitrogen can influence the production of antibiotics. In the presence of sources of nitrogen that are favorable for growth, production of many, but not all, secondary metabolites is reduced [83, 84, 85]. One interpretation of this tendency is that by supplying a good source of nitrogen, the available carbon can be used for growth and generating biomass. Thus cell does not experience or experience of lesser extent of the stringent condition in the presence of suitable nitrogen source.
Zinc is an essential trace element and cofactor required for the structure and function of many proteins. Being important, it is under tight regulation by Znr, a zinc-responsive transcriptional repressor that regulates genes encoding a high-affinity uptake system for zinc, as well as zinc-free paralogues of ribosomal proteins in many bacteria, including streptomycetes [86, 87]. Znr also directly represses a promoter within the cluster of coelibactin, a non-ribosomally synthesized peptide predicted to have siderophore (metal-chelating) activity in
Iron is another essential metal that is under tight regulation [90]. Members of the DmdR (divalent metal-dependent) family i.e., DmdR1 and DmdR2 are the key regulatory components of iron homeostasis in
One extracellular signaling molecule g-butyrolactones has been shown to regulate antibiotic production in many streptomycetes cultures [93, 94, 95]. Such a mechanism is beneficial for the community survival as extracellular signaling molecules are diffusible in solid media. This way even a single actinomycete can stimulate antibiotic production in another when grown next to each other on an agar plate [96], thus protecting the entire community against competitive microbes.
Although secondary metabolites are not considered essential for the growth and development of microorganisms, they serve diverse survival functions in nature. These molecules allowed both antagonistic and symbiotic relationships between various species from single-cell organisms to multicellular organisms. Without such relationships, the natural ecosystem whether it is soil, or lake, or forest would not be filled with rich and diverse life forms that we find on this planet. Thus, it can be said that secondary metabolites are as essential as primary metabolites in a environment with multi-species communities coexisting together.
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