Action and function of Chromobacterium violaceum in health and disease: Violacein as a promising metabolite to counteract gastroenterological diseases

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Abstract

Chromobacterium violaceum is a Gram negative, β-proteobacterium found in the microbiota of tropical and subtropical environments. Although considered an opportunistic pathogen, infection rapidly progress to fatal sepsis, with metastatic abscesses. It is noteworthy the multidrug resistant phenotype of C. violaceum and the possibility of relapse. Recently, an influence of global climate in the incidence of cases beyond the previous areas has been observed. Furthermore, chronic granulomatous disease has been considered a risk factor to infection. Despite the increase in C. violaceum infection incidence and high mortality, most clinicians are not familiar with it. This review pointed out important features of this life threatening microorganism, including its pathogenicity, mechanistic aspects, genetic and drug resistance associated factors, and the clinical association with chronic granulomatous disease. In addition, its main metabolite violacein may be a promising agent to counteract gastroenterological diseases, such as colorectal cancer and inflammatory gastric lesions.

Introduction

Secondary metabolites have a privileged place in microbiology since the discovery of penicillin by Fleming, which pave the way for the identification of a valuable number of medicinal compounds. It is therefore expected that tropical regions may contribute with a biodiversity with potential biotechnological and pharmaceutical applications [1]. In fact, nature still is an inexhaustible source of microbial diversity awaiting exploration, and Chromobacterium violaceum is one of its treasures described more than a century ago, together with its main metabolite violacein, identified as responsible for the violet colour of the bacteria colonies. In 1976, C. violaceum was first isolated in the borders and water of the Negro river (Amazon, Brazil), leading to the characterization of the photobiological properties of violacein, [3-(1,2-dihydro-5-(5-hydroxy-1H-indol-3-yl)-2-oxo-3H-pyrrol-3-ilydene)-1,3-dihydro-2H-indol-2-one]. As a consequence of this preliminary studies and its high abundance in the Amazon region, this bacterium and its main metabolite have been studied in Brazil for the last four decades and more recently it has attracted interest from the scientific community worldwide [2], [3], [4], [5]*.

Chromobacterium violaceum is a Gram-negative, rod-shaped, motile, non-fastidious, non-sporing, facultatively anaerobic, fermentative and positive for catalase and oxidase bacterium, widely distributed in the microbiota of tropical and subtropical regions. When incubated in nutrient agar, blood agar or MacConkey agar media, it produces colonies with a dark purplish colour in the pigmented strain due to its metabolite, violacein [6], [7]*. However, pigment production cannot be considered a trait of pathogenicity, since nonpigmented strains may have similar virulence [8], [9], [10], [11]. Microorganism identification depends on the biochemical characterization, although detection using multiplex polymerase chain reaction targeting the prgI, spaO, invG, and sipB genes and sequencing of the 16S rDNA gene have been demonstrated [12], [13].

Although this microorganism is not damaging to plants, and is only opportunistic to animals and humans, the infection may rapidly progress to life threatening sepsis, representing a difficult-to-treat entity. Moreover, there is a rise in the number of patients who presented with C. violaceum infection beyond the bacterium previous tropical and subtropical ecosystems [5]*, [7]*, [14]. This is of most importance since the geographic distribution of the bacterium may follow changes in global warming [7].

It is worth noting that genetic studies of C. violaceum, mainly conducted by the Brazilian National Genome Sequencing Consortium using the ATCC 12472 strain in 2003, revealed important characteristics of the microorganism, supporting its adaptability to the environment. In addition, these studies also provided information about the pathogenicity, metabolism, host interaction and violacein biosynthesis [15]. Accordingly, this strain was demonstrated to contain a circular chromosome of 4,751,080 bp and a G + C content of around 64,83%. Interestingly, these studies also revealed that several mechanisms contribute to C. violaceum coping with the plethora of stressors present in Negro river environment, such as high temperatures, lack of nutrients, high levels of radiation and toxic agents, thus justifying its abundance in this region [15]. In addition, the molecular mechanisms associated with its pathogenicity were proposed on the basis of the analysis of genes encoding possible virulence factors [15]. An important finding of this study was the presence of ORFs enconding type III secretory systems (T3SS or TTSS). T3SS is encoded by the Chromobacterium pathogenicity islands 1 and 1a (Cpi-1/-1a), and is involved in the translocation of proteins into the cell cytosol, where they take advantage of cellular signal transduction cascades for the pathogen benefit [16], [17]*. The Cpi-1/-1a-encoded T3SS is a chief inducer of cell death in a murine model of C. violaceum infection and in cultured mammalian cell lines, through the formation of pore structures in the host cell membrane [18]. Recently, these same authors demonstrated that CilA is a major regulator of the T3SS and they further characterized an effector protein translocated by this system, CopE (Chromobacterium outer protein E), which is a guanine nucleotide exchange factor (GEF) for Rac1 and Cdc42, thus playing a key role in bacterial infection of epithelial cells [17]. In addition, genes encoding factors associated with adherence and invasion process, synthesis of lipopolysaccharide (LPS) and peptidoglycan, and cytolytic proteins, such as hemolysin-like proteins, were reported [15]. Recent studies using mass spectrometry demonstrated the presence of hemolysin, collagenase, flagellar protein, metallopeptidases, outer membrane proteins, as well as the type IV secretory system (T4SS) effector protein in the culture medium of C. violaceum [19], [20].

Section snippets

Pathogenicity of Chromobacterium violaceum

Despite the ample distribution of C. violaceum in Negro river, which is a source of drinking water for the population, this saprophyte bacterium rarely infects humans, with most cases occurring in immunocompromised individuals or children [21]. This was suggested to be related to the lack of some invasion systems currently found in other proteobacteria, such as Salmonella typhimurium and Yersinia pestis [15]. However, infections have been reported to cause skin lesions, meningitis,

Drug resistance in Chromobacterium violaceum

Due to the still limited number of cases, results of antimicrobial susceptibility testing vary among different clinical settings. In this respect, most strains of C. violaceum are resistant to penicillins and beta-lactam antibiotics, such as cephalosporin, due to its increased levels of beta-lactamase [7]*, [24]*. Also, this bacterium has shown resistance to rifampin and vancomycin, which makes the treatment difficult [28]. On the other hand, susceptibility to chloramphenicol, trimethoprim,

Application of C. violaceum secondary metabolite, violacein, in anticancer therapy

A number of studies in the literature have pinpointed the biological potential and clinical significance of the main metabolite of C. violaceum characterized to date, known as violacein. Despite the research involving violacein activites in the defense mechanisms of the bacteria against eukaryotic predation and fungal disease, this purple metabolite has attracted more interest for its potential pharmacological activities, including antitumoral, antibacterial, antiprotozoal, antiviral,

Summary

Whilst C. violaceum is a rare entity, infection with this pathogen may become emergent after climate change. Thus, clinicians must be aware of its diagnosis and optimal antimicrobial therapy. Moreover, further studies will provide additional clues on the mechanisms involved and risks of infection. Secondary metabolites from natural sources have increased the human life span during the last centuries, helping to revolutionize the practice of medicine. Microbes have provided leads to the

Practice points

  • C. violaceum infection has a major impact in public health due to the high frequency of hematogenous dissemination to visceral organs and relapse, the high mortality rate and its multidrug resistant phenotype.

  • Malnourished and immunocompromised individuals, such as patients with chronic granulomatous disease, are predisposed to C. violaceum infection.

  • Violacein is a promissor biological tool in anticancer therapy, the most studied feature of this metabolite, including the gastrointestinal

Research agenda

  • C. violaceum infection may become emergent after climate change.

  • The mechanisms associated with C. violaceum infection needs to be further defined.

  • Therapeutic guidelines based on antimicrobial susceptibility tests need to be defined.

  • Further studies are necessary to clarify violacein in vivo activities and its toxicological profile.

  • The role of violacein in C. violaceum needs to be defined.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgement

Support from FAPESP (Process number 2008/51116-0), CNPq, CAPES, FINEP, INOMAT (MCTI/CNPq; Process number 573644/2008-0), NanoBioss/Sisnano (MCTI/CNPq; Process number 402280/2013-0) and Brazilian Network of Nanotoxicology (MCTI/CNPq; Process number 552120/2011-1) is acknowledged. The authors are grateful to Prof. Maikel Peppelenbosch (Erasmus MC - University Medical Center Rotterdam, The Netherlands) for valuable comments on the manuscript.

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