They consist of a single KS domain that catalyzes a defined number of elongations, usually generating small phenols or naphtol rings. The enzyme transfers the acyl group from the CoA to the active site histidine, which is a highly conserved residue. Importantly, independent of the mechanistic or structural differences, all the PKs synthetized by PKS enzymes follow the same decarboxylative condensation mechanism of the acyl-CoA precursors.
Below, a brief description is provided on the main catalytic features of PKS domains. This process involves two steps, i. This protein belongs to a highly conserved carrier family, and consists of 70— amino acid residues Byers and Gong, ACP modulates three important events during PK biosynthesis.
First, it allows the condensation during chain elongations since it transfers the starter unit from the AT domain to the KS domain. Second, it shuttles the growing chain between the up and downstream domains, as well as to optional PKS domains, probably involving protein—protein recognition between domains. Third, it prevents premature cyclization and enolization of the PK chain Yadav et al. Only when both units are covalently attached onto the module, a decarboxylative Claisen condensation occurs, which involves two conserved his residues.
Therefore, mechanistically the KS domain acts at three stages: acylation, decarboxylation and condensation Chen et al. Additionally, some KR domains are equipped with epimerase activity. The epimerizing module has a more open architecture, enabling the catalytic epimerization of methyl groups in acyl-ACP substrates, a reaction that involves the conserved serine and tyrosine residues which are also employed during ketoreduction Ostrowski et al.
The ER domain is an optional tailoring unit involved in the final oxidation state of the growing PK. Termination of PK biosynthesis involves the Te domain, which produces macrolactones via intramolecular cyclization or linear PKs by hydrolysis Keatinge-Clay, In both events, an acyl-Te intermediate is formed through the transfer of the PK chain from the last ACP to the active serine on Te domain Jenner, The processing component acts after the initial assembly when the cyclized or PK intermediate is still attached to the ACP.
To date, in P. TABLE 2. Polyketide synthases in P. PKS-based biosynthetic pathways in P. Sorbicillinoids: Despite the fact that this cluster is also present in industrial strains of P. The absence of the gene encoding for an isoepoxidon dehydrogenase agrees with the fact that this fungi does not produce patulin Samol et al. However, under laboratory conditions, yanuthone D is also not detected in this fungus Salo, Andrastin A: P.
Adapted from Staunton and Weissman , Maskey et al. Fungal terpenoids or isoprenoids are structurally diverse molecules derived from isoprene units C5 carbon skeleton : isopentenyl pyrophosphate IPP and dimethylallyl pyrophosphate DMAPP , which are synthetized in the mevalonate pathway from acetyl-CoA Chiang et al. Eventually, these linear chains of different length are further modified by cyclases, terpene synthases TPs and prenyl transferases PTs , yielding different subclasses of terpenoids Schmidt-Dannert, ; Chen et al.
For instance, monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenoids, and triterpenoids, which harbor two to six isoprene units, respectively Soltani, Terpenoids are oxygenated derivatives of terpenes, which are also derived of isoprene Stashenko and Martinez, Terpene synthases catalyze cyclization reactions forming the carbocation by substrate ionization class I or substrate protonation class II Zhou et al. Recently, the prx1 to prx4 gene cluster involved in the biosynthesis of PR-toxin in P.
This cluster contains the gene prx2 ari1 that encodes for a aristolochene synthase which forms a sesquiterpene aristolochene derivative precursor of PR-toxin.
Interestingly, an orthologous gene cluster was identified in P. Natural products represent a broad range of molecules produced by animals, plants and microorganisms. These molecules may display different biological activities e. With respect to antibiotics, most of the chemical scaffolds used today were discovered during the golden age of antibiotics discovery —s. This was followed by four decades during which hardly any new scaffolds from a natural source were developed Reen et al.
However, there is also a current understanding that only a small fraction of the potential possible molecules has been discovered to this date. This follows from genomic studies revealing large numbers of uncharacterized BGCs, while many of these gene clusters are not expressed silent or sleeping gene clusters under laboratory conditions Brakhage and Schroeckh, Furthermore, metagenomics studies indicate that the majority of microbes present in the environment have not been cultured nor characterized.
Thus, there are many challenges that need to be overcome in order to harness the natural diversity of NPs, to cultivate potential strains under laboratory conditions and to activate the BGCs for expression. To achieve the synthesis of new NPs, three main approaches Figure 7 were used in recent years, which may be successfully applied in P.
Regulatory targets and strategies to engineer P. Under natural conditions, fungi face a variety of biotic and abiotic conditions to survive. The cellular response to the environment involves complex regulatory networks that respond to stimuli such as light, pH, availability of carbon and nitrogen sources, reactive oxygen species, thermal stress, and interspecies-crosstalk Brakhage, ; Reen et al.
This strategy is derived from the observation that changes in the metabolic output of microorganisms can be achieved by alternating the medium composition and other cultivation parameters. It is well known that glucose, ammonium, or phosphate at high concentrations act as repressors of secondary metabolism, whereas iron starvation and nitrogen limitation can stimulate secondary metabolite production. The latter is for instance exploited for the production of terrain by A.
This strategy can readily be implemented using high-throughput methods, where an array of culture conditions can be screened for new metabolite profiles Spraker and Keller, In combination with bioinformatics tools, this strategy can be a powerful tool to investigate the production of new molecules, as exemplified by the discovery of aspoquinolones A—D in A.
However, despite the fact that the OSMAC approach has led to the discovery of increased numbers of new molecules with antimicrobial activity, some chemical and physical conditions are still missing under the laboratory tested conditions as the activation often concerns a limited number of BGCs Chiang et al.
The production of secondary metabolites is a natural strategy that microorganisms have developed to cope with specific environmental conditions and challenges. They serve as intermediary agents to establish a symbiotic association between species or as a weapon against other organism to compete for nutrients and space. Interestingly, the association of two marine organisms, Emericella sp.
Also, the interactions between fungi and insects result in the production of volatile secondary metabolites Rohlfs and Churchill, Nonribosomal peptide synthetase and PKS are highly structured and multi-facetted enzymes, containing a tremendous potential for the exploitation of their product scaffold structure for the generation of novel, bioactive compounds.
However, due to the complexity of all interactions within these mega enzymes, the elucidation and implementation of engineering strategies is an extremely challenging task. Several strategies have been developed and applied with different degrees of success, though the overall approaches can be grouped as module, domain, sub-domain or site directed, respectively.
Owing to their large size, utilization of a random mutagenesis approach proved to be difficult, but other more directed strategies are met with a great success. Multiple studies confirmed that the substrate specificity of a NRPS A-domain can be successfully altered, however, at the cost of substantially lowered catalytic velocity Thirlway et al. Similar successes and limitations were observed when domains were swapped or replaced by synthetic versions Beer et al.
The most challenging way of obtaining novel NRPS, however, is the swapping or combining of entire modules Kries, Domain swapping overall created not only functional parts or domains, but also complete NRPS though with limited success Beer et al. Due to the strict arrangement of NRPS in domains and modules, the possibility of exchanging a unit appears to be the most straight forward approach for altering its intrinsic properties.
A series of studies targeting the enzymes linked to the production of daptomycin Nguyen et al. The daptomycin biosynthetic cluster comprises three NRPS containing a total of 13 modules for the incorporation of an equal number of substrates. Different levels of domain and module swap approaches were followed, starting with the exchange of modules 8 and 11 C-A-T , representing an internal module exchange. The resulting NRPS exhibited the production of novel daptomycin compounds with an inverted amino acid composition at the predicted sites at a near native rate Nguyen et al.
A similar combinatorial approach has been chosen for altering the PK stereochemistry. In Aspergillus , this rational domain swap has also been used to diversify the native substrates that NR-PKS takes as starter unit to produce new products.
Another mechanism to stimulate the expression of silent BGCs in P. The regulation of BGCs is effected at many levels, through specific or local and global regulators up to epigenetic regulation involving the modification of the chromatin landscape Lim et al.
Pleiotropic transcriptional regulators or global regulators are proteins that respond to environmental signals such as pH, temperature, and N- and C-sources. They provide the link between the production of secondary metabolites and external cues. In fungi, these proteins control the regulation of BGCs that do not contain other regulatory factors.
Additionally, global regulators also act on genes that do not belong to secondary metabolism Brakhage, ; Rutledge and Challis, ; Fischer et al. Global regulators that have been reported as key players in the biosynthesis of secondary metabolites are featured below. This heterotrimeric complex is a conserved regulator present in most of the fungi, except yeast.
Likewise, this complex provides a link between sexual development and secondary metabolism through light regulation Yin and Keller, ; Deepika et al. The role of the velvet complex in secondary metabolism mostly follows from the control that the LaeA protein executes on several BGCs in filamentous fungi. LaeA l oss of a flR e xpression- A was identified in as a global regulator in Aspergillus.
Deletion of this gene results in the repression of many BGC, such as the one responsible for the production of penicillin, lovastatin, and sterigmatocystin. Overexpression of LaeA causes an opposite phenotype. It has been hypothesized that LaeA acts at different levels, i. Structurally, LaeA has a S -adenosyl methionine SAM -binding site with a novel S -methylmethionine auto-methylation activity, although this activity does not seem to be essential for its function.
LaeA is not a DNA-binding protein, but it does affect chromatin modifications. In an A. The heterochromatic marks stay until the sterigmatocystin cluster is activated, and apparently LaeA influences the offset of these marks in this particular cluster Reyes-Dominguez et al.
Orthologs of LaeA have been discovered in many other filamentous fungi as Penicillium , Fusarium , Trichoderma , Monascus spp. For instance, LaeA1 of F. Interestingly the stimulation of these genes was not directly influenced by the methylation of H3K4 or H3K9 Wiemann et al. LaeA is not the only member of the velvet complex that has influence on the regulation of secondary metabolite production.
VeA of A. This study also revealed that veA modulates the biosynthesis of fumagillin via the regulation of FumR, a transcriptional factor of the fumagillin cluster, which in turn is also regulated by LaeA. Similarly, a transcriptome analysis in A.
Likewise, orthologs of veA are also present in other fungi such as in P. Despite the clear interaction between veA and LaeA in the velvet complex and its influence on secondary metabolism, it is thought that veA may be acting as molecular scaffold of the velvet complex, since it interacts also with three other methyl transferases [LaeA-like methyltransferase F LlmF , velvet interacting protein C VipC , and VipC associated protein B VapB ].
This suggests that veA functions in a supercomplex or in dynamic network control. Taken together, modulation of the velvet complex is a useful tool to activate BGCs Sarikaya-Bayram et al. Basic leucine zipper bZIP transcription factors are highly conserved in the eukaryotes.
The dimeric bZIP transcriptional factors play an important role in the cellular responses to the environment. Regarding their structure, they contain a conserved leucine zipper domain and a basic region, which controls the dimerization of the protein and establishes sequence-specific DNA-binding, respectively.
In fungi, bZIP proteins have been implicated in multiple metabolic processes, such as in the regulation of development, morphology and in stress responses. Several orthologs of the Yap family bZIPs, which were first described in yeast, have been characterized in Aspergillus spp. AtfA, NapA, Afyap1, Aoyap1, and Apyap1 and these regulators have recently been associated with the production of secondary metabolites in filamentous fungi.
However, these transcription factors also display negative regulation. For instance, an increase in the biosynthesis of aflatoxin and chratoxin has been observed when yap1 is deleted in A. Its function is associated in nitrogen regulation and has a negative effect on the biosynthesis of aflatoxin in A. Likewise, it is involved in the repression of nitrogen metabolism when ammonium or glutamine are present.
Recently, this transcription factor and its orthologs have been shown to influence secondary metabolism. For instance, areA deletion strains of F. In Acremonium chrysogenum , the deletion of areA resulted in the reduction of cephalosporin because of a reduced expression of the enzymes involved in cephalosporin biosynthesis. Additionally, AreA is a positive regulator of the production of gibberellins, trichothecene deoxynivalenol DON , fusarielin H, beauvericin and zearalenone Li et al.
The carbon catalytic repressor CreA also influences secondary metabolism. CreA is a Cys 2 His 2 zinc finger transcription factor that is involved in the repression of genes associated with the use of carbon sources other than glucose Knox and Keller, CreA has been implicated in the variable metabolite profiles when fungi are grown in the presence of different carbon sources Yu and Keller, Recently, the xylanase promoter binding protein Xpp1 of Trichoderma reesei was used as a reporter to fulfill a dual role in the regulation of primary and secondary metabolism.
Xpp1 is an activator of primary metabolism, while its deletion boosts the production of secondary metabolites, including sorbicillinoids Derntl et al. Another Cys 2 His 2 zinc finger transcription factor conserved in fungi is PacC, which is involved in pH dependent regulation. Deletion of the ortholog of this gene BbpacC in Beauveria bassiana resulted in a loss of dipicolinic acid insecticide compound and oxalic acid production, compounds that reduce the pH of the medium.
However, also production of a yellow pigment was noted. When A. Whereas in F. In addition to the global regulators, the expression of BGCs can be also modulated by specific regulatory elements, which most of the times are encoded by genes that are part of the same cluster that they regulate.
In some cases, such regulators also influence the expression of other BGCs. There are three sub regions: a linker, a zinc finger and a dimerization domain.
Additional to a DBD, these proteins contain two further functional domains, the acidic region and the regulatory domain.
These transcription factors can act as monomers, hetero- and homodimers. They recognize single or multiple trinucleotide sequences, commonly CCG triples, in a symmetric or asymmetrical format. The transcriptional activity of these proteins is regulated by phosphorylation, exposing the activation and DNA binding domains for DNA binding MacPherson et al. Some of these regulators have been shown to control the expression of BGCs. For instance, in F. Interestingly, fumonisin production is also regulated by another Zn 2 Cys 6 protein that is encoded by a gene located outside of the fumonisin cluster Flaherty and Woloshuk, Mlcr is another example of a positive regulator that controls compactin production in P.
Likewise, some BGCs encode multiple regulatory proteins. Next to the aflR gene in the aflatoxin cluster resides the aflS formerly aflJ gene. The corresponding transcription factor binds to AflR to enhance the transcription of early and mid-biosynthetic genes in the aflatoxin pathway Georgianna and Payne, ; Yin and Keller, Also, regulation of BGCs via crosstalk has been observed in filamentous fungi.
For instance, the alcohol dehydrogenase promoter has been used to induce the expression of putative pathway-specific regulatory gene scpR in A. For some regulators, no clear phenotype is observed.
It is a classical strategy that consists of the abolishment of the expression of a certain gene by its elimination whereupon the impact on the metabolite profile is examined by HPLC or LC-MS. A major limitation of this approach is that it can only be used in BGCs that are not totally silenced under laboratory conditions.
Using this strategy, it was possible to elucidate the highly branched biosynthetic pathway for the synthesis of roquefortine as well as the biosynthetic pathways of sorbicillinoids and chrysogine in P. Likewise, this approach can be used to remove transcriptional repressor genes, as in the case of TetR-like pathway-specific repressor proteins, whose deletion induced the production of gaburedins in Streptomyces venezuelae Rutledge and Challis, Global regulators, such as LaeA have also been targeted using this strategy Chiang et al.
Another method concerns the replacement of the endogenous promoter of the gene s in a BGC by a strong constitutive or inducible promoter. For instance in A. Additionally, it also led to the expression of the asperfuranone BGC, which is normally silent Bergmann et al.
Recently in P. This included the analysis of four constitutive promoters from P. This approach is one of the most used strategies to turn on cryptic BGCs, since a change in expression level of a regulator may boost the expression of a whole cluster.
Usually, this strategy is applied in combination with the promoter replacement approach. Using this strategy, i. This resulted in the production of aspyridones A and B Bergmann et al. Similarly when the global regulator FfSge, which is associated with vegetative growth of F.
This chromatin structure consists of a basic unit called nucleosome, which consists of superhelical DNA base pairs that binds an octamer of four different core histone proteins two each of H2A, H2B, H3, and H4 in 1. It has been shown that modifications of the chromatin structure boosts or alters changes gene expression, amongst other genes involved in the biosynthesis of secondary metabolites. Structurally, chromatin represents an obstacle that complicates access of DNA-binding factors to their corresponding binding regions.
According to the compaction level, chromatin can be in a dense heterochromatin or relaxed euchromatin state. These compaction levels are regulated by post-translational modification of the histone proteins by acetylation, methylation, ubiquitination, ethylation, propylation, butylation, and phosphorylation events. Regions that display low transcriptional activity have been associated with the heterochromatic conformation. In contrast, the euchromatic conformation is present in regions with abundant coding sequences and is usually highly active during transcription.
Such regions are also linked with hyper-acetylated nucleosomal histones. Likewise, it has been reported that methylation of H3K9, H3K27, and H4K20 are typical markers of the heterochromatin, while in euchromatin methylation occurs at H3K4 Brosch et al.
As mentioned above, LaeA influences secondary metabolite production through chromatin modification. The methylation state of H3K9 has been correlated with the heterochromatin protein A HepA , since this protein needs the di- and tri- methylation of H3K9 for binding to chromatin and to form heterochromatin.
Deletion of LaeA allows the unobstructed binding of HepA to the AlfR promoter, thereby affecting the expression of the sterigmatocystin pathway. The deletion of the methyltransferase encoding c lrD and ezhB genes in Epichloe festucae , that act on H3K9 and H3K27, respectively in axenic culture , results in the activation of the ergot alkaloids and lolitrem BGCs. These compounds are necessary to establish a symbiotic association with the plant Lolium perenne. Compass complex of proteins associated with Set1 which methylates H3K4 in yeast, also impacts secondary metabolism in filamentous fungi.
The deletion of one of its components cclA in A. Likewise, in F. Other types of histone modification may alter the chromatin landscape, such as acetylation which is a reversible process governed by two antagonist enzymes: histone acetyltransferases HATs and deacetylases HDACs.
Active transcription is usually associated with histone acetylation, although recently the deacetylation of histones has been shown to cause activation of genes Brosch et al.
Indeed, the interaction between A. HdaA is a class 2 histone deacetylase involved in the regulation of BGCs that are located near the telomeres, such as the penicillin and sterigmatocystin clusters in A. Indeed, deletion of the hdaA gene results in the increased and early gene expression of these two BGCs, and the production of the corresponding secondary metabolites.
In contrast, HdaA overexpression shows the opposite effect Shwab et al. Histone deacetylases are ubiquitously distributed in filamentous fungi, and therefore HDAC inhibitors can be used to improve the synthesis of NPs by epigenome manipulation Shwab et al.
For instance, the metabolite profile of Cladosporium cladosporioides and A. An exploratory analysis performed in 12 fungi treated with different types of DNA methyltransferase and histone deacetylase inhibitors, revealed the production of new secondary metabolites but also the elevated amounts of known compounds Williams et al.
In this respect, the chromatin state can directly influence the binding of transcription factors, and thereby modulate expression Palmer and Keller, ; Macheleidt et al. It has been hypothesized that histone sumoylation may modulate secondary metabolite production. This process is mediated by a small protein termed SUMO small ubiquitin-like modifier that shares structural similarity to the ubiquitin protein. Many fungal BGCs are located in distal regions of the chromosomes. In these heterochromatin rich regions, transcription of the BGCs can be activated by epigenetic regulation.
Therefore, the encoding genes of proteins that influence histone modification are prime targets, although these modifications can also be achieved by chemical treatment Williams et al. A recent study in P. Secondary metabolites produced by fungi can be toxic to the producer organisms, and often fungi are equipped with detoxification mechanisms. One of these mechanisms is toxin excretion by transporters, which are membrane proteins whose genes often localize to the BGCs. Since biosynthesis of secondary metabolites may take place in different cell compartments, also intracellular transport may be evident Kistler and Broz, Despite their assumed biological importance, the deletion of transporter genes from the BGCs often does not impact secondary metabolite production.
For instance, deletion of the A. Probably, this protein is redundant, and other transporters may participate in excretion, detoxification or self-defense. Similarly, the tri12 gene contained in the trichothecene BGC encodes for a membrane protein required for the biosynthesis of trichothecene and virulence of F. Often, however, the deletion of the transporter gene in BGCs has no effect on production. Possibly, these metabolites are also recognized by other promiscuous transporters, or transporters that are not part of the BGC Keller, However, the expression of the zra1 gene is regulated by the transcriptional factor ZEB2, whose gene localizes to the corresponding BGC Lee et al.
Also, the penicillin BGC of P. Furthermore, compartmentalization of the biosynthesis of penicillin is well documented requiring transport of penicillin precursors across the membrane of intracellular organelles Weber et al. Several approaches have been used to activate the expression of cryptic BGCs in a targeted manner. Usually, this is achieved by manipulation of pathway-specific regulatory genes, or by replacing endogenous promoters for inducible systems or strong promoters Rutledge and Challis, The various approaches are summarized in Figure 7.
Due to the increasing number of sequenced filamentous fungi, it is necessary to make use of efficient genome editing tools to explore new potential sources of secondary metabolites. For many years, the unique strategy available for the genome edition of P. This strategy allowed for the generation P. This study demonstrated that the deletion of full gene clusters is feasible with minimal cloning efforts, which opens the possibilities to engineer new synthetic pathways and the re-factoring P.
Basically, this concept is derived from the activation of the actinorhodin BGC in S. Another successful examples in the BGCs activation have been reported by modifying the transcription and translation pathways via targeting different ribosomal proteins, RNA polymerases RNAP and translation factors Ochi and Hosaka, Due to the broad range of molecular tools available to express heterologous pathways in yeast, several attempts have been undertaken to express NRPS and PKS genes with the remainder of the pathway in yeast Rutledge and Challis, Although the first step was performed when the acetyl-CoA:isopenicillin N acyltransferase IAT , which catalyzes the last step in the penicillin biosynthesis was amplified from the P.
Alternatively, fungi may be used as platform organism, as it was for instance demonstrated with the reconstruction of the citrinin gene cluster of Monascus purpurea in A. Likewise, the in vivo assembly of genetic elements has been successfully applied in P. The potential of this approach follows a recent study employing A. Such methods can contribute to product identification but also to the production of unique compounds by introduction of specific tailoring enzymes.
Specifically, this involves the expression of pathways from a plasmid in a suitable production host and a screen for product formation. For many years P. Its genome sequence revealed an unexplored potential of P. Despite the development of bioinformatics tools for genome mining of BGCs to identify novel molecules Blin et al.
However, most of the secondary metabolite associated genes in P. Given the urgent need for new molecules based on novel chemical scaffolds for the use in the medical and biotechnological fields e.
Here, we have summarized the main approaches that have been applied for P. However, the combinatorial swapping strategy of structural elements such as recognition regions has increased the perspectives for designing de novo biosynthetic pathways. To mine the secondary metabolome of filamentous fungi, general methods such as manipulating cultivation conditions have been used that can also be implemented as a high-throughput strategy. Another avenue is interfering with the genetic regulatory systems, either through the manipulation of specific or global regulators.
This strategy also revealed crosstalk between certain BGCs and an important role of chromatin remodeling in BGC expression. This is further stimulated by the development of a synthetic biology toolbox using promoters and terminators as building blocks and more complex regulatory devices to control the expression of genes. Importantly, the in vivo assembly of genetic elements in P. In particular the low cost of DNA synthesis will allow rapid progress using such approaches as exemplified by a study using A.
A further challenge is the generation of a platform strain in which endogenous BGCs have been removed to allow for more optimal carbon and nitrogen flow toward the production of the compounds of interest.
Such a Penicillium platform might be used as a heterologous host to express a vast arsenal of BGCs from others filamentous fungi and represents a good alternative to yeast as expression host, an organism that does not naturally produce NRP and PK. The use of a such industrial strains to rapidly achieve the high level production of a novel metabolite has proven to be successful for pravastatin production McLean et al. Despite the progress in genetic engineering and bioinformatics tools to identify BGCs, the main bottleneck to identify potentially interesting compounds has not yet been solved.
Bioinformatic tools perform poorly in the prediction of the structures formed, and therefore future discovery programs will mostly dependent on high throughput methods to express foreign pathways and then use advanced metabolomics to identify the novel products.
Since such approaches depend on high throughput, further efforts are needed to implement high throughput cloning methods to P. FG-C and RZ wrote the manuscript. AD supervised, conceived, and designed the manuscript. RB co-supervised the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Although human infections with P. Written informed consent was obtained from the kin of the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal form. A Manual of the Penicillia. Co, Google Scholar. J Clin Microbiol. J Infection.
Article Google Scholar. Ouchterlony O: Antigen-antibody reactions in gels. Acta Pathol Microbiol Scand. Appl Environ Microbiol. Brouwer J: Cross-reactivity between Aspergillus fumigatus and Penicillium.
Int Arch Allergy Immunol. South Med J. Ann Hematol. Article PubMed Google Scholar. Emphasis on microbiological spectra, patient outcome and prognostic factors. Antimicrob Agents Chemother. Download references. We are grateful to Prof.
Katsuhiko Kamei Chiba University for his guidance and invaluable advice. We declare no financial support. You can also search for this author in PubMed Google Scholar.
Correspondence to Naomi Tsurikisawa. CO examined the patient and contributed to manuscript preparation. NT examined the patient, took part in discussions about the patient, and was involved in manuscript preparation and editing. AS performed the tests for antigen-specific precipitating antibodies to A.
MW and YK confirmed the fungus as P. KT and MT identified the fungus as P. All authors read and approved the final manuscript. Reprints and Permissions. Oshikata, C. Fatal pneumonia caused by Penicillium digitatum : a case report. BMC Pulm Med 13, 16 Download citation. Received : 14 October Accepted : 14 March Published : 23 March Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Metulae are secondary branches that form on conidiophores. The metulae carry the flask-shaped phialides. The organization of the phialides at the tips of the conidiophores is very typical. The conidia 2. In its filamentous phase, Penicillium marneffei is microscopically similar to the other Penicillium species. Intracellular arthroconidial yeast-like cells are observed inside the macrophages in infected tissues [ ].
Paecilomyces Gliocladium Scopulariopsis. Penicillium differs from Paecilomyces by having flask-shaped phialides and globose to subglobose conidia; from Gliocladium by having chains of conidia; and from Scopulariopsis by forming phialides. Penicillium marneffei differs as well by its thermally dimorphic nature. Available data are very limited. For Penicillium chrysogenum , MICs of amphotericin B , itraconazole , ketoconazole , and voriconazole are acceptably low, while the denoted MICs for Penicillium griseofulvum are higher than those for Penicillium chrysogenum [ ].
Notably, Penicillium marneffei isolates may yield considerably high MICs for amphotericin B, flucytosine , and fluconazole and relatively low MICs for itraconazole, ketoconazole, voriconazole, and terbinafine [ , , , ]. Further data are required to provide a more precise susceptibility profile for various Penicillium spp.
Amphotericin B, oral itraconazole, and oral fluconazole have so far been used in treatment of penicilliosis marneffei [ , , ]. Oral itraconazole was found to be efficient when used prophylactically against penicilliosis marneffei in patients with HIV infection [ ].
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