Coagulase-negative staphylococci release a purine analog that inhibits Staphylococcus aureus virulence

Chin, Denny; Goncheva, Mariya I.; Flannagan, Ronald S.; Deecker, Shayna R.; Guariglia-Oropeza, Veronica; Ensminger, Alexander W.; Heinrichs, David E.

doi:10.1038/s41467-021-22175-3

Cited by 35 publications

(22 citation statements)

References 56 publications

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Section: Discussionmentioning

confidence: 99%

“…Arising from studies to uncover the therapeutic potential of bactericidal and bacteriostatic compounds produced by coagulase-negative staphylococci (CoNS) to compete with S. aureus in shared ecological niche, the Heinrich’s group identified the CoNS-produced purine analogue 6-thioguanine (6-TG) and revealed its potential to both inhibit growth of S. aureus by interfering with ribosome biogenesis and downregulate agr -controlled virulence under purine limited growth conditions (67). Resistance to 6-TG can arise through mutations in PbuG (also named StgP, 6-thioguanine permease) and the Hpt hypoxanthine phosphoribosyltransferase (53), demonstrating that guanine/6-TG are transported and metabolised by PbuG/StgP and Hpt, respectively.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Purine nucleosides interfere with c-di-AMP levels and act as adjuvants to re-sensitise MRSA to β-lactam antibiotics

Nolan¹,

Zeden²,

Campbell³

et al. 2022

Preprint

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Elucidating the complex mechanisms controlling mecA/PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) has the potential to identify new drug targets with therapeutic potential. Here, we report that mutations that interfere with de novo purine synthesis (pur operon), purine transport (NupG, PbuG and PbuX) and the nucleotide salvage pathway (DeoD2, Hpt) increased β-lactam resistance in MRSA strain JE2. Extrapolating from these findings, exogenous guanosine and xanthosine, which are fluxed through the GTP branch of purine biosynthesis were shown to significantly reduce MRSA β-lactam resistance. In contrast adenosine, which is fluxed to ATP, significantly increased oxacillin resistance, whereas inosine, which can be fluxed to ATP and GTP via hypoxanthine, only marginally reduced the oxacillin MIC. Increased oxacillin resistance of the nupG mutant was not significantly reversed by guanosine, indicating that NupG is required for guanosine transport, which in turn is required to reduce β-lactam resistance. Suppressor mutants resistant to oxacillin/guanosine combinations contained several purine salvage pathway mutations, including nupG and hpt. Microscopic analysis revealed that guanosine significantly increased cell size, a phenotype also associated with reduced levels of c-di-AMP. Consistent with this, guanosine significantly reduced levels of c-di-AMP, and inactivation of GdpP, the c-di-AMP phosphodiesterase negated the impact of guanosine on β-lactam susceptibility. PBP2a expression was unaffected in nupG or deoD2 mutants suggesting that guanosine-induced β-lactam susceptibility may result from dysfunctional c-di-AMP-dependent osmoregulation. These data reveal the therapeutic potential of purine nucleosides as β-lactam adjuvants that interfere with the normal activation of c-di-AMP required for high-level β-lactam resistance in MRSA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Purine nucleosides interfere with c-di-AMP levels and act as adjuvants to re-sensitise MRSA to β-lactam antibiotics

Nolan¹,

Zeden²,

Campbell³

et al. 2022

Preprint

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“…are abundant colonizers of the normal microflora of humans and animals [ 1 ]. Despite living in commensalism with the host, staphylococci, in particular, Staphylococcus aureus , can cause a wide spectrum of infections [ 2 ]. The Staphylococcus genus comprises the coagulase-negative staphylococci (CoNS) and coagulase-positive staphylococci (CoPS) [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, recent studies have shown that CoNS have an increasing clinical impact and can act as opportunistic pathogens, particularly in immunocompromised patients [ 1 , 4 , 5 , 6 ]. Staphylococci can easily acquire antimicrobial resistance genes, preventing the treatment of some infections [ 2 ]. Over the last few decades, methicillin-resistant S. aureus (MRSA) have been a leading cause of nosocomial infections and an emergent zoonotic pathogen [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Nocturnal Birds of Prey as Carriers of Staphylococcus aureus and Other Staphylococci: Diversity, Antimicrobial Resistance and Clonal Lineages

Silva

Lopes²,

Soeiro³

et al. 2022

Antibiotics

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Owls are nocturnal predators that inhabit urbanized and farmlands. They are in direct contact with other animals, both livestock and small wild rodents that they mostly feed on. Staphylococci can be both commensal and pathogenic bacteria that are widespread across the various ecological niches. We aimed to isolate staphylococci from owls and to characterize their antimicrobial resistance, virulence factors and genetic lineages. Swab samples were collected from the throat and cloaca of 114 owls admitted to two rehabilitation centers in Portugal. The identification of staphylococci species was performed by MALDI-TOF. Staphylococci antimicrobial resistance and virulence genes were investigated by means of the disk diffusion method and PCR. Staphylococcus aureus isolates were characterized by MLST, agr and spa-typing. Of the tested animals, 66 isolates were recovered, including 10 different species of staphylococci, of which 25 were coagulase-positive (CoPS) and 41 were coagulase-negative (CoNS). Twenty-three S. aureus were isolated, of which one mecC-MRSA was identified. The isolates were mainly resistant to penicillin, aminoglycosides, clindamycin and tetracycline. mecC-MRSA belonged to ST1245 and spa-type t843 and the remaining S. aureus were ascribed to 12 STs and 15 spa types. A high diversity of clonal lineages was identified among the S. aureus isolated from wild owls. Owls feed mainly on small rodents often exposed to waste and anthropogenic sources, which may explain the moderate prevalence of S. aureus in these animals.

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“…Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-containing cyclic peptide antibiotic that prohibits colonization by S. aureus [ 32 ]. Quite a number of CoNS produce 6-thioguanine (6-TG), a purine analog that suppresses S. aureus growth by inhibiting de novo purine biosynthesis and is also effective in wound healing [ 33 ]. Other CoNS produce lantibiotics such as epidermin and gallidermin, which inhibit cell wall biosynthesis and have broad-spectrum activity against Gram-positive pathogens [ 34 , 35 ], or antimicrobial peptides (AMPs) that selectively kill S. aureus and synergize with the human AMP LL-37 [ 36 ].…”

Section: Positive Effect Of Some Commensals and Probiotics On Wound Healingmentioning

confidence: 99%

The Ambivalent Role of Skin Microbiota and Adrenaline in Wound Healing and the Interplay between Them

Luqman

Götz

2021

IJMS

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After skin injury, wound healing sets into motion a dynamic process to repair and replace devitalized tissues. The healing process can be divided into four overlapping phases: hemostasis, inflammation, proliferation, and maturation. Skin microbiota has been reported to participate in orchestrating the wound healing both in negative and positive ways. Many studies reported that skin microbiota can impose negative and positive effects on the wound. Recent findings have shown that many bacterial species on human skin are able to convert aromatic amino acids into so-called trace amines (TAs) and convert corresponding precursors into dopamine and serotonin, which are all released into the environment. As a stress reaction, wounded epithelial cells release the hormone adrenaline (epinephrine), which activates the β2-adrenergic receptor (β2-AR), impairing the migration ability of keratinocytes and thus re-epithelization. This is where TAs come into play, as they act as antagonists of β2-AR and thus attenuate the effects of adrenaline. The result is that not only TAs but also TA-producing skin bacteria accelerate wound healing. Adrenergic receptors (ARs) play a key role in many physiological and disease-related processes and are expressed in numerous cell types. In this review, we describe the role of ARs in relation to wound healing in keratinocytes, immune cells, fibroblasts, and blood vessels and the possible role of the skin microbiota in wound healing.

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Coagulase-negative staphylococci release a purine analog that inhibits Staphylococcus aureus virulence

Cited by 35 publications

References 56 publications

Purine nucleosides interfere with c-di-AMP levels and act as adjuvants to re-sensitise MRSA to β-lactam antibiotics

Purine nucleosides interfere with c-di-AMP levels and act as adjuvants to re-sensitise MRSA to β-lactam antibiotics

Nocturnal Birds of Prey as Carriers of Staphylococcus aureus and Other Staphylococci: Diversity, Antimicrobial Resistance and Clonal Lineages

The Ambivalent Role of Skin Microbiota and Adrenaline in Wound Healing and the Interplay between Them

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