Bacterial Persister cell infections by auranofi n?

Bacterial persister cells, tolerant to antibiotics, are an isogenic subpopulation of cells, which possess characteristics distinct to those of their wild type counterparts. Persister cells have been recognized in a wide range of genera and species, including, but not limited to Staphylococcus spp., such as S. aureus, S. epidermidis, and S. capitis; Salmonella serovars, including Salmonella Typhi; Pseudo- monas spp. such as P. aeruginosa; Burkholderia spp. such as B. cepacia and B. pseudomallei; Vibrio spp. such as V. cholerae; Shigella spp.; Brucella spp. such as B. melitensis; Escherichia spp. such as E. coli; Serratia spp. such as S. marcescens; Lactobacillus spp. such as L. acidophilus as well as Neisseria spp. such as N. gonorrhoeae [1–3]. Bacterial persister cells are characterized by a slow-growing phenotype and low metabolic activity, that is, persister cells divide at a considerably slower rate compared to the rate of logarithmic bacterial growth. In fact, some bacterial persister cells are “dormant”; that is, the cells do not undergo cell division [4]. In these dormant bacterial persister cells, cellular metabolism is reduced even further than in slow-growing cells, in some instances leading to the cells being described as ‘non-growing’ or ‘metaboli- cally inactive’, despite the fact that dormant persister cells, like all living cells, still require some form of cellular energy and redox homeostasis to maintain cell viability, even in the absence of growth (i.e. No cell division) [5]. Bacterial persister cells are important in microbial pathogenicity because they are extremely resistant to antimicrobials, and are especially associated with recurrent infections and latent [6]. The basis for bacterial persister cell antimicrobial resistance is multifactorial. For example, the absence or the slow rate of cell division in persister cells means that several of the biosynthetic pathways targeted by known antimicrobial drugs are not in active use, making the persister cell ‘indifferent’ to the effects of the antibiotic. Accordingly, bacterial persister cells are frequently able to persist inside the defense mechanisms of the host cell, likely contributing to the persister cell’s resistance to antimicrobials [1,5]. These properties, together with the fact that bacterial persister cells have been isolated from abscesses, blood, soft tissues, bones, joints and the respiratory tract of patients, mean that persister cells are clinically significant microorganisms.
Auranofin is able to inhibit the activity of glycine reductase by forming a stable bond with inorganic selenium, disrupting selenium metabolism and the synthesis of selenocysteine. Without selenocysteine, bacteria cannot synthesise glycine reductase, and are therefore unable to reduce glycine for energy production [6,7]. Clostridium difficile uses the selenoprotein proline reductase for
energy production. The activity of proline reductase is also inhibited by auranofin in a similar fashion to glycine reductase [8]. Auranofin has been shown to inhibit the growth of T. denticola and C. difficile in vitro at low micromolar concentrations. Debnath et al. and Harbut et al. [9,10] reported that auranofi n exhibits its antimicrobial activity through the inhibition of the thioredoxin reductase (TrxR) enzyme in both E. histolytica and S. aureus. However, a crystallographic study conducted by Parsonage et al. [11], revealed that auranofin most likely does not bind to the cysteine residues in TrxR of E. histolytica. Another study, conducted by Thangamani et al., also demonstrated that TrxR is not the primary target of auranofin in bacteria. We demonstrated that auranofin inhibits multiple biosynthetic pathways, including DNA, protein and cell wall synthesis in bacteria. However, the exact molecular target of auranofin, in bacteria, still remains unclear [12].
Staphylococcal persister cells have been associated with a wide range of infections and conditions. Staphylococcal persister cells include small colony variants, initially named because the colonies are typically approximately one-tenth the size of their wild-type counterparts because of their slow growth rate. Of particular clinical concern are S. aureus persister cells, which show increased resistance to some antimicrobial drugs such as aminoglycosides (i.e. gentamicin) compared to parental strains. S. aureus persister cells have been associated with numerous persistent and recurrent S. aureus infections, including, but not limited to, respiratory infections in cystic fi brosis (CF) patients, osteomyelitis, skin infections and infections associated with medical implants. Though S. aureus is typically an extracellular organism, S. aureus persister cells can inhabit intracellularly, therefore contributing to their ability to cause persistent and recurrent infections [13,14]. Staphylococcal persister cells, such as S. aureus persister cells, are typically associated with auxotrophism for hemin, menadione or thiamine, which are related to mutations in genes encoding products involved in the electron transport system, such as the hemB, menD, and ctaA genes. Other phenotypic characteristics of these auxotrophic S. aureus persister cells can include, but are not limited to reduced hemolytic activity, reduced pigment formation and decreased coagulase activity. In some instances, S. aureus persister cells are thymidine-dependent, having a defect in their thymidine biosynthetic pathway. Such persister cells are especially associated with long-term trimethoprim-sulfamethoxazole (SXT) treatments of patients with cystic fibrosis, wherein thymidine- dependent SXT-resistant persister cells multiply and emerge in the

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respiratory tract after SXT treatment to suppress infections in these patients. The clinical importance of persister cells means that there is a need for improved methods for killing or inhibiting the growth of persister cells and for treating and or preventing conditions, diseases associated with them [15,16]. Auranofin is an oral gold-containing drug originally approved and used through- out the USA and EU for the treatment of rheumatoid arthritis [17]. Recent studies have shown that auranofin also possesses potent antiparasitic [18] and antibacterial activities [17,19] for instance against Methicillin-resistant Staphylococcus aureus and Streptococ- cus pneumonia [17,20]. Recent studies by Harbut et al. [17] and Aguinagalde et al. [20] show that auranofin has been used with success in the treatment of invasive staphylococcal infections. However, the effi cacy of auranofin in the treatment of infections caused by staphylococcal Persister cells remains unexplored.

Funding

This project is supported by funds provided by Hamadan University of Medical Sciences.

Transparency declarations

None to declare. References
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Babak Asghari*
Department of Microbiology, School of Medicine, Hamadan University
of Medical Sciences, Hamadan, Iran
Hamid Reza Sadeghi
Department of Medical Physics, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
Hamzeh Mazaherylaghab
Department of English, School of Medicine, Hamadan University of
Medical Sciences, Hamadan, Iran

* Corresponding author. E-mail addresses: [email protected],[email protected]
(B. Asghari).

Received 25 April 2017

Please cite this article in press as: B. Asghari, et al., Combatting Bacterial Persister cell infections by auranofin?, Biomed Pharmacother (2017), http://dx.doi.org/10.1016/j.biopha.2017.07.022