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Cysteine-Capped Hydrogels Incorporating Copper as Effective Antimicrobial Materials against Methicillin-Resistant Staphylococcus aureus.

ABSTRACT: Methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) has become an alarming threat to public health, and infected soft tissue. Antibiotics are commonly used to treat skin infection with MRSA, but the inappropriate use of antibiotics runs a considerable risk of generating resistant S. aureus. In this study, we created a cysteine-capped hydrogel able to absorb and release copper, an ion with the capability of suppressing the growth of USA300, a community-acquired MRSA. The results of analysis of Fourier transform infrared spectroscopy (FTIR) revealed the binding of copper to a cysteine-capped hydrogel. The topical application of a cysteine-capped hydrogel binding with copper on USA300-infected skin wounds in the dorsal skin of Institute of Cancer Research (ICR) mice significantly enhanced wound healing, hindered the growth of USA300, and reduced the production of pro-inflammatory macrophage inflammatory protein 2-alpha (MIP-2) cytokine. Our work demonstrates a newly designed hydrogel that conjugates a cysteine molecule for copper binding. The cysteine-capped hydrogel can potentially chelate various antimicrobial metals as a novel wound dressing.

SUBMITTER: Yang JJ

PROVIDER: S-EPMC7074715 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Cysteine-Capped Hydrogels Incorporating Copper as Effective Antimicrobial Materials against Methicillin-Resistant Staphylococcus aureus.

Yang John Jackson JJ Huang Yung-Chi YC Chuang Tsung-Hsien TH Herr Deron Raymond DR Hsieh Ming-Fa MF Huang Chun-Jen CJ Huang Chun-Ming CM

Microorganisms 20200121 2

Methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) has become an alarming threat to public health, and infected soft tissue. Antibiotics are commonly used to treat skin infection with MRSA, but the inappropriate use of antibiotics runs a considerable risk of generating resistant S. aureus. In this study, we created a cysteine-capped hydrogel able to absorb and release copper, an ion with the capability of suppressing the growth of USA300, a community-acquired MRS ...[more]

PMID: 31973160

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Project description:BackgroundInhibition and eradication of Staphylococcus aureus biofilms with conventional antibiotic is difficult, and the treatment is further complicated by the rise of antibiotic resistance among staphylococci. Consequently, there is a need for novel antimicrobials that can treat biofilm-related infections and decrease antibiotics burden. Natural compounds such as eugenol with anti-microbial properties are attractive agents that could reduce the use of conventional antibiotics. In this study we evaluated the effect of eugenol on MRSA and MSSA biofilms in vitro and bacterial colonization in vivo.Methods and resultsEffect of eugenol on in vitro biofilm and in vivo colonization were studied using microtiter plate assay and otitis media-rat model respectively. The architecture of in vitro biofilms and in vivo colonization of bacteria was viewed with SEM. Real-time RT-PCR was used to study gene expression. Check board method was used to study the synergistic effects of eugenol and carvacrol on established biofilms. Eugenol significantly inhibited biofilms growth of MRSA and MSSA in vitro in a concentration-dependent manner. Eugenol at MIC or 2×MIC effectively eradicated the pre-established biofilms of MRSA and MSSA clinical strains. In vivo, sub-MIC of eugenol significantly decreased 88% S. aureus colonization in rat middle ear. Eugenol was observed to damage the cell-membrane and cause a leakage of the cell contents. At sub-inhibitory concentration, it decreases the expression of biofilm-and enterotoxin-related genes. Eugenol showed a synergistic effect with carvacrol on the eradication of pre-established biofilms.Conclusion/major findingThis study demonstrated that eugenol exhibits notable activity against MRSA and MSSA clinical strains biofilms. Eugenol inhibited biofilm formation, disrupted the cell-to-cell connections, detached the existing biofilms, and killed the bacteria in biofilms of both MRSA and MSSA with equal effectiveness. Therefore, eugenol may be used to control or eradicate S. aureus biofilm-related infections.

Project description:Urinary tract infection (UTI) is one of the most common infectious conditions affecting people in the United States and around the world. Our knowledge of the host-pathogen interaction during UTI caused by Gram-positive bacterial uropathogens is limited compared to that for Gram-negative pathogens. Here, we investigated whether copper and the primary copper-containing protein, ceruloplasmin, are mobilized to urine during naturally occurring UTI caused by Gram-positive uropathogens in patients. Next, we probed the role of copper resistance in the fitness of methicillin-resistant Staphylococcus aureus (MRSA) during experimental UTI in a murine model. Our findings demonstrate that urinary copper and ceruloplasmin content are elevated during UTI caused by Enterococcus faecalis, S. aureus, S. epidermidis, and S. saprophyticus. MRSA strains successfully colonize the urinary tract of female CBA mice with selective induction of inflammation in the kidneys but not the bladder. MRSA mutants lacking CopL, a copper-binding cell surface lipoprotein, and the ACME genomic region containing copL, exhibit decreased fitness in the mouse urinary tract compared to parental strains. Copper sensitivity assays, cell-associated copper and iron content, and bioavailability of iron during copper stress demonstrate that homeostasis of copper and iron is interlinked in S. aureus. Importantly, relative fitness of the MRSA mutant lacking the ACME region is further decreased in mice that receive supplemental copper compared to the parental strain. In summary, copper is mobilized to the urinary tract during UTI caused by Gram-positive pathogens, and copper resistance is a fitness factor for MRSA during UTI. IMPORTANCE Urinary tract infection (UTI) is an extremely common infectious condition affecting people throughout the world. Increasing antibiotic resistance in pathogens causing UTI threatens our ability to continue to treat patients in the clinics. Better understanding of the host-pathogen interface is critical for development of novel interventional strategies. Here, we sought to elucidate the role of copper in host-Staphylococcus aureus interaction during UTI. Our results reveal that copper is mobilized to the urine as a host response in patients with UTI. Our findings from the murine model of UTI demonstrate that copper resistance is involved in the fitness of methicillin-resistant S. aureus (MRSA) during interaction with the host. We also establish a critical link between adaptation to copper stress and iron homeostasis in S. aureus.

Project description:Methicillin resistant Staphylococcus aureus (MRSA) infection is becoming refractory to existing antibiotic therapy owing to the inherent ability of S. aureus to develop rapid resistance and is considered a major threat to public health. We found that a natural isolate of Bacillus pumilus from the Columbia River Estuary produces a strong anti-MRSA compound, amicoumacin A. As amicoumacin A has been reported to exhibit anti-microbial, anti-inflammatory, and anti-ulcer activities, we sought to uncover its mechanism of action. Genome-wide transcriptome analysis of S. aureus COL in response to amicoumacin A showed alteration in the expression of genes involved in several cellular processes including cell envelope turnover, cross-membrane transport, virulence, metabolism, and general stress response. The most highly induced gene was lrgA, encoding an antiholin-like product, which has been shown to be induced in response to a collapse of membrane potential. In order to gain further insight into the mechanism of action of amicoumacin A, a whole genome comparison of wild-type COL and amicoumacin A-resistant mutants isolated by serial passage method was carried out. Single point mutations resulting in codon substitutions were uncovered in several distinct genes: ksgA, RNA dimethyltranferase; fusA, elongation factor G; dnaG, primase, ; lacD, tagatose 1,6-bisphosphate aldolase, ; and SACOL0611, encoding a putative glycosyl transferase gene. Based on these results, a candidate approach was undertaken to recreate the same amino acid substitution individually in FusA and KsgA, each of which resulted in two-fold resistance towards amicoumacin A. The fusA gene is known as the site for fusidic acid- resistant mutations; however the codon substitutions in EF-G that cause amicoumacin A resistance and fusidic acid resistance occur in separate domains and do not bring about cross resistance. Taken together, these results suggest that amicoumacin A might cause perturbation of the cell membrane and lead to energy dissipation. Decreased rates of cellular metabolism including protein synthesis and DNA replication in resistant strains might allow cells to compensate for membrane dysfunction and thus increase cell survivability.

Dataset Information

Cysteine-Capped Hydrogels Incorporating Copper as Effective Antimicrobial Materials against Methicillin-Resistant Staphylococcus aureus.

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Cysteine-Capped Hydrogels Incorporating Copper as Effective Antimicrobial Materials against Methicillin-Resistant Staphylococcus aureus.

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