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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 1  |  Page : 9-18

Comparative genomics of Mycoplasma: Insights on genome reduction and identification of potential antibacterial targets


Department of Bioinformatics, Bharathiar University, Coimbatore, Tamil Nadu, India

Date of Submission27-Nov-2018
Date of Decision31-Dec-2018
Date of Acceptance05-Jan-2019
Date of Web Publication13-Mar-2019

Correspondence Address:
Dr. Angamuthu Kandavelmani
W/o M. Ramachandran, 16, Gandhi Nagar, Pudhupalayam Road, Narasimma Naicken Palayam, Coimbatore - 641 031, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_142_18

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  Abstract 


Background: Mycoplasmas are cell wall-deficient bacteria which cause respiratory and urogenital infections in human. Mycoplasmas are resistant to many of the available antibiotics because of their high mutation rates and lack of cell wall. Various studies have identified the emergence of treatment-resistant Mycoplasma isolates. Novel drug target identification has become significant for the development of successful antibacterial treatments. Computational genomic analysis plays a significant role in facilitating the identification of potential drug targets in many bacterial pathogens. Methods: In the present study, 12 Mycoplasma genomes were subjected to comparative genomic analysis to reinforce the understanding of their genomic organization and to identify potential drug targets. The distributions of genes under the Clusters of Orthologous Groups of proteins (COG) functional categories were analyzed for all the 12 Mycoplasma genomes. Genes from each functional category that are conserved across all the Mycoplasma genomes were extracted to identify the backbone genome of Mycoplasma species. The genes in the backbone genome were subjected to similarity search against a database of essential genes to validate their essentiality. Essentiality of these genes was further analyzed based on their function and subcellular localization. Results: The 12 Mycoplasma genomes under study were found to exhibit marked similarities in COG functional category distributions. An overall loss of genes in various functional categories has been observed in all the 12 Mycoplasma genomes. In all the 12 Mycoplasma genomes under study, a maximum reduction in the genes involved in the secondary metabolites biosynthesis, transport, and catabolism (Q) is observed. Conclusion: Comparative genomic studies have identified a set of 170 genes which are commonly present all the 12 Mycoplasma genomes. Further analysis of these genes has identified a set of 158 core essential genes which serve as a promising cluster of novel antibacterial targets.

Keywords: Antibiotic resistance, comparative genomics, drug target, essential genes, Mycoplasma


How to cite this article:
Kandavelmani A, Piramanayagam S. Comparative genomics of Mycoplasma: Insights on genome reduction and identification of potential antibacterial targets. Biomed Biotechnol Res J 2019;3:9-18

How to cite this URL:
Kandavelmani A, Piramanayagam S. Comparative genomics of Mycoplasma: Insights on genome reduction and identification of potential antibacterial targets. Biomed Biotechnol Res J [serial online] 2019 [cited 2019 Mar 25];3:9-18. Available from: http://www.bmbtrj.org/text.asp?2019/3/1/9/254097




  Introduction Top


Mycoplasmas are the smallest known free-living organisms with extremely small genome size which are often portrayed as minimal self-replicating organisms.[1],[2] Owing to their small genome size, mycoplasmas provide researchers a unique model for the identification of the minimal gene set required for the survival of a free-living bacterium.[3],[4] Mycoplasmas have evolved from Gram-positive bacteria, through a process of reductive evolution wherein they have lost several genes involved in metabolism, cellular process and energy production, transcription regulation, cell-division, and heat-shock response.[1] Mycoplasmas make a heavy use of operon system to potentially reduce the number of regulatory elements and to increase the gene density. As mycoplasmas have limited biosynthetic capabilities, most mycoplasmas exist as parasites with strict host and tissue specificities. Mycoplasmas are widespread in nature as obligate parasites of humans, mammals, reptiles, fish, arthropods, and plants.[2]

Many of the mycoplasmas are pathogenic to human and animals. Mycoplasmas cause chronic inflammatory disease of the respiratory system, urogenital tract, and joints. As a conditional pathogen, mycoplasmas are also associated with various diseases, including pneumonia, arthritis, meningitis, and chronic urogenital tract disease.[5] Mycoplasmas are also associated with intrauterine infections and bacterial vaginosis.[6],[7],[8],[9],[10],[11],[12],[13]

Mycoplasmas lack a rigid cell wall, but instead, they possess a triple-layered limiting membrane. Hence, they do not get affected by many of the common antibiotics that target cell wall synthesis. Mycoplasmas are not susceptible to beta-lactams such as penicillin and cephalosporins which act by interfering with cell wall synthesis by inhibiting peptidoglycan polymerization. Mycoplasmas are also not susceptible to rifampicin and vancomycin which combine with cell wall substrates. However, they are susceptible to a variety of other broad-spectrum antibiotics, most of which only inhibit their multiplication and do not kill them. Tetracyclines, macrolides, and fluoroquinolones are the major antibiotics used in the treatment of mycoplasmal infections.[5] Tetracyclines are particularly used for genital tract infections, and macrolides are widely used for respiratory tract infections.

Most mycoplasmas are surface parasites and remain adhered to the surface of epithelial cells, whereas Mycoplasma penetrans penetrates into the host cell after its attachment to the host cell. In the intracellular niche, the pathogen remains well protected from the immune system and from the action of many antibiotics.[14] M. penetrans continues their colonization in the host despite the presence of specific immune response. Studies have pointed out that Mycoplasma species transform their surface antigenic molecules at a high frequency, which make them evade the host immune system.[15],[16],[17] Several studies have reported that M. penetrans may act as cofactors in the activation of the acquired immunodeficiency syndrome.[18],[19] Moreover, mycoplasmas can elicit pleiotropic immune responses. The ability of mycoplasmas to survive within the host by circumventing the host immune system makes them difficult to eliminate from patients despite appropriate antibiotic treatment. In the case of immunosuppressed or immunodeficient individuals, eradication may be further challenging.[20]

Many bacteria have acquired resistance to several antibiotics due to their prolonged use over the years. Mycoplasmas have developed resistance to various antibiotics through gene mutation and by acquisition of a resistance gene. It has been reported that mycoplasmas have developed resistance to tetracyclines due to acquisition of the tetM gene.[21] Mycoplasmas have been observed to exhibit higher mutations compared to conventional bacteria. Hence, they have a higher propensity to more rapidly develop resistance to antimicrobials. It has been evidenced that mycoplasmas have developed resistance to oxytetracycline and tylosin.[22],[23]

Antibiotic susceptibility profiles of mycoplasmas have reported that Mycoplasma hominis has acquired resistance to several antibiotics. However, it has also been observed that M. hominis exhibits more sensitivity to doxycycline when compared with other antimicrobials.[24],[25],[26] Mycoplasma genitalium which has the smallest genome among any known free-living organism is an important sexually transmitted pathogen. It is the etiologic agent of nongonococcal urethritis in men. In women, M. genitalium is associated with cervicitis and pelvic inflammatory disease. Various research works have evidenced the emergence of treatment-resistant M. genitalium isolates.[27],[28] Studies have determined that M. genitalium has acquired resistance to the macrolide antibiotic, azithromycin, and the fluoroquinolone moxifloxacin. It has been reported that M. genitalium has acquired antibiotic resistance by mutations in 23S rDNA, parC, and gyrA genes.[29]

Studies on the antibiotic susceptibility profile of Mycoplasma pneumoniae, the human respiratory tract pathogen, have reported about the emergence of certain strains with acquired resistance to macrolides worldwide.[30],[31] Acquired resistance of M. pneumoniae to macrolides and the treatment of M. pneumoniae infections have also been reviewed.[32] Eradication of mycoplasmas from human or animal hosts or from cell cultures by antibiotic treatment has become challenging because of their acquired antibiotic resistance and lack of cidal activity.

The study of mycoplasmas has become important in the understanding of chronic diseases. Mycoplasmas being both an intracellular and extracellular pathogens, a complete understanding of the disease process and virulence mechanism, would provide a way through for the identification of novel mechanisms to combat these pathogens. Mycoplasmas are difficult to culture in the laboratory because of their complex nutritional requirements and specialized requirement of growth conditions. Despite the use of metagenomic sequencing method for the identification of mycoplasmas that are not detected by conventional methods,[33],[34] a study of mycoplasmas by in silico methods remains more significant. A complete understanding of the biology of an organism necessarily starts with knowledge of its genetic makeup. The advent of new rapid sequencing methods has made available the whole genome sequences of a number of Mycoplasma species, thereby allowing for a computational insight toward understanding of their complete biology and evolutionary perspectives through comparative genomics.

With the increase in the emergence of antibiotic-resistant and multidrug-resistant bacterial pathogens, innovative approaches to the discovery of novel antibiotics have become obligatory. Drug target identification, which makes an extensive use of comparative, functional, and subtractive genomics, plays a vital role in drug and vaccine discovery process.[35],[36] In silico genomics-based approach for drug target identification has proven to be significant as it provides cost-effective screening of targets at the genome level. Moreover, it also reduces the time required to identify novel drug targets.

Mycoplasma genus currently comprises hundreds of species and subspecies which are obligate parasitic species dispersed in a wide spectrum of hosts, including humans, animals, insects, and plants. In the present study, whole genome sequences of 12 Mycoplasma species, namely Mycoplasma agalactiae, Mycoplasma arthritidis, Mycoplasma capricolum, Mycoplasma gallisepticum, M. genitalium, M. hominis, Mycoplasma hyopneumoniae, Mycoplasma mycoides, M. penetrans, M. pneumoniae, Mycoplasma pulmonis, and Mycoplasma synoviae, were subjected to comparative genomic analysis studies. These species represent a diverse group of mollicutes that vary in host range. The availability of complete genome sequences of these species reinforces comparative genomic studies that allow a better understanding of their genomic organization, metabolism, and interaction with their hosts. The 12 Mycoplasma genomes were subjected to comparative genomic analysis to reinforce the understanding of their genomic organization and to identify potential drug targets.


  Methods Top


[Figure 1] provides a Schematic representation of the methods employed in Mycoplasma Genome Analysis. The project was approve by Bharathiar University, Coimbatore, Tamil Nadu, India.
Figure 1: Schematic representation of Mycoplasma genome analysis

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Genome sequence data

The genome sequences and annotations of 12 Mycoplasma s – M. agalactiae PG2 (NC_009497.1), M. arthritidis 158 L3-1(NC_011025.1), M. capricolum subsp. Capricolum ATCC 27343 (NC_007633.1), M. gallisepticum str. R (low) (NC_004829.2), M. genitalium G37 (NC_000908.2), M. hyopneumoniae J (NC_007295.1), Mycoplasma mobile 163K (NC_006908.1), M. mycoides subsp. mycoides SC str. PG1 (NC_005364.2), M. penetrans HF-2(NC_004432.1), M. pneumoniae M129 (NC_000912.1), M. pulmonis UAB CTIP (NC_002771.1), and M. synoviae ATCC 25204 (NZ_CP011096.1) – were retrieved from the genome database of the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov/genome).

Gene density

Gene density of a genome is a measure of the number of genes per million base pairs (megabase, Mb). For all the 12 Mycoplasma genomes under study, gene density was calculated. Distribution of the genes in Mycoplasma genomes was analyzed based on their gene densities.

Analysis of distribution of genes by functional category

The Clusters of Orthologous Groups of proteins (COGs) database[37] was used to analyze the gene categories of Mycoplasma genomes. The distributions of genes under the COG functional categories were analyzed for all the 12 Mycoplasma genomes. The number of genes in each COG category was tabulated and plotted. The functional categories that are conserved or lost altogether or show a massive reduction in certain genomes were analyzed separately.

Extraction of backbone genome

The complete list of genes under each of the COG functional categories was compared in all the 12 Mycoplasma genomes. Genes from each functional category that are conserved across all the Mycoplasma genomes were extracted. These genes are described to form the backbone genome of Mycoplasma species. The complete list of genes composing the backbone genome was tabulated and their COG functional category distributions were analyzed.

Essentiality of the backbone genome

Essential genes are genes that are obligatory for the survival of a living cell. These genes comprise a minimal gene set required for an organism to sustain cellular life. The database of essential genes (DEG) holds information on essential genes (http://tubic.tju.edu.cn/deg/).[38] The genes comprising the backbone genome were subjected to similarity search against DEG to validate their essentiality.

Function identification and subcellular localization prediction

Essentiality of the genes comprising the backbone genome was further analyzed based on their function and subcellular localization. The functional role of these genes in various metabolic pathways was obtained from the pathway database of Kyoto Encyclopedia of Genes and Genomes. Protein subcellular localization prediction (PSL-pred), a system vector machine-based method, was employed for the prediction of the subcellular localization of the essential proteins. PSL-pred predicts five major subcellular localizations (cytoplasm, outer membrane, inner membrane, extracellular, and periplasmic) of Gram-negative bacteria (http://www.imtech.res.in/raghava/pslpred/).[39]


  Results Top


Genome size, number of genes, and gene density

The number of protein-coding genes per genome ranges from 475 to 1037 in the mycoplasmas under study [Table 1]. All the 12 mycoplasmas of the present study are pathogens with a wide spectrum of host range. Diseases caused by mycoplasmas in their specific hosts are provided in [Table 2]. In all the 12 mycoplasmas under study, a marked decrease in the number of genes with the reduction of genome size has been observed [Figure 2]. A maximum reduction in genome size with the least number of genes is observed in M. genitalium.
Table 1: Genome information of Mycoplasma

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Table 2: Pathogenicity of Mycoplasma

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Figure 2: Genome size versus number of genes in Mycoplasma genomes. Kbp – genome length in kilobase pairs; number of genes – total number of genes in the genome. Number of genes decreases with the reduction in genome size

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Gene density of a genome is a measure of the number of genes per million base pairs (megabase, Mb). Gene densities of prokaryotes are comparatively much higher than that of eukaryotes. In the Mycoplasma genomes under study, the gene density ranges from 786 to 903. M. genitalium with the smallest genome has the highest gene density of 903. M. agalactiae with the genome size of 0.88 Mb also had the same gene density of 903. Among the mycoplasmas under study, M. penetrans with the largest genome size of 1.36 Mb has the least gene density of 786. However, in other genomes, no strong correlation is observed between the genome size and the gene density [Table 3] and [Figure 3]. To more closely analyze the genetic makeup of the Mycoplasma genomes, the distribution of genes by functional categories across the genomes was carried out using the COG database.
Table 3: Gene density of Mycoplasma genomes

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Figure 3: Genome size versus gene density in Mycoplasma genomes, Kbp – genome length in kilobase pairs; number of genes – total number of genes in the genome. No correlation is observed between the genome size and gene density

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Clusters of Orthologous Groups of proteins functional category distribution and analysis

The COGs database provides a framework for analyzing the orthologous relationship among completely sequenced genomes. The 12 Mycoplasma genomes exhibit marked similarities in COG functional category distributions [Figure 4], [Figure 5] and [Table 4].
Figure 4: Distribution of Clusters of Orthologous Groups of proteins categories and their percentage representation in Mycoplasma genomes. Mycoplasma genomes exhibit marked similarities in Clusters of Orthologous Groups of proteins functional category distributions

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Figure 5: Distribution of Clusters of Orthologous Groups of proteins categories in 12 Mycoplasma genomes

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Table 4: Distribution of the Clusters of Orthologous Groups of proteins functional categories in the Mycoplasma genomes

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Genes involved in basic cellular processes of information storage and processing, namely transcription, translation, and replication, contribute to around 20%–30% of the total number of genes in the Mycoplasma genomes. In all the 12 Mycoplasma genomes, around 13%–20% of the genes are involved in translation (J). The percentage of genes involved in transcription (K) is comparatively lower ranging from 2% to 4% all the 12 Mycoplasma genomes. Genes involved in replication, recombination, and repair (L) contribute to around 6%–11% of the total genes. Owing to the essential role of these basic cellular processes, evolutionary deletion of genes in these categories had to be very limited and selective. An overall conservation in the percentage of genes involved in information storage and processing is observed in all the 12 Mycoplasma genomes. In all the 12 Mycoplasma genomes, percentage of genes in the function unknown (S) category ranges from 2% to 5%. Genes involved in translation (J), replication, recombination and repair (L), posttranslational modification, protein turnover, chaperones (O), energy production and conversion (C), and carbohydrate transport and metabolism (G) show a marked increase in their percentage representation per genome in almost all the 12 Mycoplasma genomes. Owing to the massive reduction of Mycoplasma genomes during the course of their degenerative evolution from Gram-positive bacteria, an overall loss of genes in other functional categories is observed in the Mycoplasma genomes under study.

Genes involved in RNA processing and modification (A), chromatin structure and dynamics (B), nuclear structure (Y), cell motility (N), cytoskeleton (Z), and extracellular structures (W) are completely lost in all Mycoplasma genomes under study. In all the 12 Mycoplasma genomes under study, a maximum reduction in the genes involved in secondary metabolites biosynthesis, transport, and catabolism (Q) is observed whereas these secondary metabolite genes are absent in the genomes of M. arthritidis, M. hyopneumoniae, and M. synoviae.

Backbone genome analysis was carried out to identify the genes conserved across Mycoplasma genomes. The complete list of genes under each of the COG functional categories was compared in all the 12 Mycoplasma genomes. Genes from each functional category that are conserved across all the Mycoplasma genomes were extracted. A set of 170 genes was found to be commonly present all the 12 Mycoplasma genomes. These genes are described to form the backbone genome of mycoplasmas. The distribution of genes of the backbone genome into COG functional categories is shown in [Figure 6].
Figure 6: Clusters of Orthologous Groups of proteins category distribution in backbone genome. The backbone genome comprises genes from the Clusters of Orthologous Groups of proteins functional categories of J, K, L, D, M, U, O, C, G, E, F, H, I, P, and R. Genes involved in cellular process and signaling and information storage and processing form the major constituent of the backbone genome. Comparatively, metabolic genes have a minor contribution toward the backbone genome

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The backbone genome comprises genes from the COG functional categories of J (translation), K (transcription), L (replication, recombination, and repair), D (cell cycle control, mitosis, and meiosis), M (cell wall/membrane biogenesis), U (Intracellular trafficking and secretion), O (posttranslational modification, protein turnover, and chaperones), C (energy production and conversion), G (carbohydrate transport and metabolism), E (amino acid transport and metabolism), F (nucleotide transport and metabolism), H (coenzyme transport and metabolism), I (lipid transport and metabolism), P(inorganic ion transport and metabolism), and R (general functional prediction only). Genes involved in cellular process and signaling and information storage and processing form the major constituent of the backbone genome. Comparatively, metabolic genes have a minor contribution toward the backbone genome. This is in accordance with the fact that mycoplasmas have lost several genes involved in metabolic pathways, thereby depending on their hosts for the supply of nutrients.

Backbone genome and gene essentiality

Backbone genome of mycoplasmas mainly contains those genes involved in fundamental cellular processes. Compared to the other functional categories, translation (J) genes form the major component of the backbone genome. Essential genes are indispensable to support cellular life. Essential genes determined by various experimental techniques in different organisms have been collated by DEG. To validate the essentiality of the genes comprising the backbone genome, these genes were subjected to similarity search against DEG. Genes that share similarity with DEG are regarded as essential and those genes without significant similarity are regarded as nonessential. Among the 170 genes of the backbone genes, 158 genes are found to be essential. Genes comprising the backbone genome, their COG numbers and their essentiality are summarized in [Table 5]. The complete list of the genes comprising the backbone genome, their COG numbers, and their essentiality is provided in [Supplementary Table 1]. The subcellular locations of these essential genes predicted using PSL-pred, their protein product, and their functions are listed in [Supplementary Table 2]. This set of genes inferred based on COG and DEG analysis represents the conserved essential gene set indispensable for the survival of these mollicutes.
Table 5: Essential genes of Mycoplasma identified from the backbone genome

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  Discussion Top


The advent of robust sequencing methods has increased the availability of whole genome sequences of mycoplasmas, thereby reinforcing comparative genomic studies to facilitate a better understanding of these bacteria. Mycoplasmas are obligatory parasites restricted to vertebrate hosts. Mycoplasmas have lost several genes involved in metabolism, cellular process, and energy production during their degenerative evolution from Gram-positive bacteria.[1] Investigation on gene content evolution in mycoplasmas has substantiated the degradation of metabolic capabilities in these bacteria during lineage.[40]

Mycoplasmas, characterized by their smaller genome size, are extensively used as model organisms to identify the minimal gene set required for the survival of a free-living bacterium. Mycoplasmas have evolved by drastic reduction in their genome size, thereby losing many genes involved in various biosynthetic pathways.[2],[40]

A maximum reduction in genome size with the least number of genes is observed in M. genitalium. M. genitalium has the smallest genome of any known free-living organism. It has been suggested that the smallest genome size of M. genitalium may be in close approximation with the minimal gene set required for the survival of a free-living bacterium. In 1996, Mushegian and Koonin compared the genome of M. genitalium with that of Haemophilus influenzae and anticipated that a set of 256 genes is a close approximation of a minimal gene set for bacterial life.[41]

Since mycoplasmas are obligatory parasites depending on their hosts for many of their nutritional requirements, biosynthesis of secondary metabolites has become dispensable.[2] Systematic comparison of the distribution of genes in various COG functional categories of the two closely related species, M. genitalium and M. pneumoniae, showed marked deviations in certain functional categories. The genomes of M. genitalium and M. pneumoniae exhibit discernible similarities in the distribution of genes in various COG functional categories. However, M. genitalium shows a maximum reduction in the genes belonging to the functional categories of defense mechanisms (V), carbohydrate transport and metabolism (G), and amino acid transport and metabolism (E). Gene loss in these functional categories of M. genitalium could be a result of its adaptation to a more parasitic intracellular life.[42]

Backbone genome refers to the core genome which contains a subset of genes present in all genomes under investigation. Identification of genomic core among a taxonomic group is vital for understanding their genomic diversity and evolution. Identification of essential gene set provides a way through in identifying novel drug targets and to identify minimal gene set required for survival of an organism.[43] Identification of essential gene set could also contribute to the construction of more suitable cellular chassis to be used in various biotechnology applications.[44],[45] Degenerative evolution of mycoplasmas has reduced their genome size. With respect to broad host range and host-specific adaptations, mycoplasmas exhibit an enormous genetic diversity.[46] However, it has been previously reported that differential gene loss in microbial genomes is dependent on environmental niche.[47]

All of the conserved essential genes identified in the present study were found to encode for cytoplasmic proteins involved in various metabolic pathways. These results suggest that the conserved essential gene set identified in the present study could be used as potential targets in the development of novel antibiotics. Essential genes have widespread applications in the emerging field of synthetic biology, identification of minimal genomes, and in the understanding of the universal principles of life. Since essential genes encode for fundamental cellular functions that are indispensable for the survival of the organism, they could be used as promising targets in the development of novel antimicrobials.[48],[49] Thus, the set of 158 core essential genes identified in the present study serves as a promising cluster of novel antibacterial targets.


  Conclusion Top


The conserved essential gene set identified in the present study is indispensable for the survival of these mollicutes as these genes are commonly shared by all the 12 Mycoplasma genomes. The conserved essential genes could have an effective use in studies emphasizing the genome compaction of mycoplasmas. These conserved essential genes could play a significant role in the rapidly emerging field of synthetic biology and in the development of novel antimicrobials. The targets identified in the present study could be effectively used for the development of novel drugs that could be used specifically for the treatment of mycoplasmal infections.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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