Search

Methicillin-resistant Staphylococcus aureus (MRSA) colonization increases infection risk in both patients and healthy individuals. Decolonization therapy has been proven to reduce S. aureus infections, but data on the effectiveness of individual decolonization strategies in community-onset MRSA carriage are scarce. The aim of this narrative review was to summarize the evidence on strategies for the elimination of MRSA colonization in community-onset MRSA carriers. PubMed database was searched for studies on MRSA eradication, from inception to July 2023. Topical therapy is proven to be effective in nasal-only carriage and in temporary load reduction. Mupirocin nasal ointment in combination with chlorhexidine body wash is highly effective in nasal-only MRSA carriers in the community as well. In patients with extra-nasal colonization, addition of orally administered antibiotics likely increases success rates compared with topical therapy alone. Studies on systemic treatment of extra-nasal MRSA decolonization are subject to a high heterogeneity of antimicrobial agents, treatment duration, and control groups. The majority of evidence supports the use of a combination of topical therapy with rifampin and another antimicrobial agent. Decolonization treatment with probiotics is a promising novel non-antibiotic strategy. However, achieving long-term decolonization is more likely in countries with low MRSA prevalence, given the risk of recolonization in a context of high MRSA prevalence. The decision to pursue community-onset MRSA eradication treatment in the individual patient should be based on the combination of the treatment objective (short-term bacterial load reduction in health care settings vs. long-term eradication in community settings), and the likelihood of successful decolonization. The latter is influenced by both individual risk factors for treatment failure, and the risk of recolonization. The addition of a combination of systemic antibiotics is rational for extra-nasal long-term decolonization. To determine the most effective systemic antimicrobial agents in MRSA decolonization, more research is needed. [ABSTRACT FROM AUTHOR]

[Display omitted] Transdermal drug delivery represents a promising avenue for the treatment of dermatologic diseases, such as cutaneous melanoma and skin infections. This study involves the development of a novel therapeutic strategy that employs a skin-penetrating peptide SPACE-modified flexible liposomal chrysomycin A (CA@SPACE-LP) with a particle size of 111.5 nm. In vitro transdermal experiments demonstrated that CA@SPACE-LP was effective in enhancing the ability of the drug to penetrate the stratum corneum and enter deep into the skin tissue, increasing the intradermal drug concentration up to threefold compared to free CA. Furthermore, CA@SPACE-LP was observed to maintain the biological activity of CA against planktonic Methicillin-resistant Staphylococcus aureus (MRSA) and melanoma cells. In vivo studies demonstrated that the topical administration of CA@SPACE-LP was efficacious in controlling the progression of cutaneous melanoma, with a tumor suppression rate of approximately 60 %, which was more pronounced than that observed with intravenous Taxol. Furthermore, CA@SPACE-LP demonstrated efficacy in the management of intradermal MRSA infections, with a significantly reduced area of ulceration in the treated mice (0.25 cm2) compared to the positive control drug (Mupirocin Ointment). These results suggest that the topical delivery system developed in this study has the potential to be used for the simultaneous treatment of skin cancer and invasive MRSA infection. [ABSTRACT FROM AUTHOR]

[Display omitted] • Series of novel ursolic acid derivatives were designed and synthesized. • Derivatives 27 and 34 had an MIC value of 1 μM against MRSA. • Derivatives 27 and 34 could disrupt the bacterial cell membrane. • Derivatives 27 and 34 showed good antibacterial activity against MRSA in vivo. The misuse and abuse of antibiotics have led to the increase of drug resistance and the emergence of multi-drug resistant bacteria. Therefore, it is an urgent need to develop novel antimicrobial agents to address this problem. Natural products (NPs) could provide an effective strategy for the discovery of drug due to their wide range of source and biological activities. Ursolic acid (UA) is a naturally occurring compound known for its wide range of biological properties. In this study, a series of UA derivatives were rationally designed and synthesized by incorporating antibacterial potential fragments of benzenesulfonamide and indole, with the aim of obtaining novel UA derivatives for the treatment of bacterial infections. Based on the preliminary screening, UA derivatives 27 (yield of 26 %), containing 4-chlorobenzenesulfonamide and 6-carboxyindole pharmacophores, as well as 34 (yield of 42 %), containing 4-carboxybenzenesulfonamide and unsubstituted indole pharmacophores, were identified as promising antibacterial agents against Staphylococcus aureus , especially for methicillin-resistant Staphylococcus aureus (MRSA), possessing MICs of 1 μM. Furthermore, both of them also displayed low hemolytic activity, non-resistance, and low-toxicity to mammalian cells. In addition, further mechanistic studies revealed that 27 and 34 were able to inhibit and eliminate MRSA biofilm formation, affecting the permeability of bacterial cell membrane, leading to increase intracellular reactive oxygen species (ROS) and ultimately inducing bacterial death. Notably, 27 and 34 also showed promising in vivo efficacy against MRSA in a mouse wound model. These results suggested that 27 and 34 should have promising applications against MRSA infection. [ABSTRACT FROM AUTHOR]

The biosynthesis of mupirocin, a clinically significant antibiotic produced by Pseudomonas sp. NCIMB 10586, is activated by the N -acyl homoserine lactone (AHL) MupR/I quorum sensing (QS) system. However, to date, limited research has focused on the influence of global regulators such as the GacS/A two-component system (TCS) on the MupR/I QS system or mupirocin biosynthesis. In this study, we characterized the regulatory components of the Gac/Rsm transduction system in the mupirocin-producing model strain NCIMB 10586 and investigated their interconnection with the MupR/I QS circuit and subsequent mupirocin biosynthesis. The production of mupirocin was hampered by either gacS inactivation, gacA inactivation, or the double-mutant of the sRNAs ( RsmY and RsmZ). Similarly, the expressions of mupR and mupI , and AHL synthesis significantly decreased in gacS, gacA, or rsmY/Z mutants, indicating that the GacS/A system stimulates mupirocin biosynthesis via the MupR/I QS system. Five CsrA family proteins, RsmA/E/I/F/N, were found in strain NCIMB 10586, and the single and multiple mutants of rsmA/E/I/F/N showed different phenotypes with respect to mupirocin production. Our results revealed that mupirocin biosynthesis was likely to be negatively regulated by RsmA/E/I, but positively regulated by RsmF. Additionally, the RsmF protein was shown to interact with the 5' leader of mupR mRNA. In summary, the Gac/Rsm system positively regulates the biosynthesis of mupirocin mainly through the MupR/I QS system, and the model of the regulatory mechanism is proposed. The elucidation of the Gac/Rsm-MupR/I regulatory pathway could help devise ways for improving mupirocin production through genetic engineering.IMPORTANCEThe Gac/Rsm regulatory system plays a global regulatory role in bacterial physiology and metabolism, including secondary metabolism. Mupirocin is a clinically important antibiotic, produced by Pseudomonas sp. NCIMB 10586, whose biosynthesis is activated by the MupR/I quorum sensing system. Global regulators have important impacts on the gene expression of secondary metabolic gene clusters and QS genes, and the GacS/A two-component system is one of the main regulators across Pseudomonas species, which significantly influences antibiotic production. Our study presented that the expressions of QS genes and mup gene cluster were downregulated in gacS, gacA, or rsmY/Z mutants compared to the wild-type. The inactivation of rsmA/E/I/F/N in NCIMB 10586, encoding CsrA family proteins, showed different regulatory traits of mupirocin production, in which the RsmF protein could interact with the 5' UTR region of mupR mRNA. These findings provide the understanding of the regulatory role of Gac/Rsm on mupirocin biosynthesis and mupR/I QS system and lay foundations for further improving mupirocin production.