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Effect of MRSA on CYP450: dynamic changes of cytokines, oxidative stress, and drug-metabolizing enzymes in mice infected with MRSA

Huaqiao Tang,Nana Long,Lin Lin,Yao Liu,Jianlong Li,Fenghui Sun,Lijuan Guo,Fen Zhang,Min Dai

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a very damaging and widespread pathogen, which is associated with many diseases and causes serious infections. MRSA infection can modulate the effects of drugs, which may occur through an influence on cytochrome P450 (CYP450), the drug-metabolizing enzyme in the liver. In this study, we evaluated the underlying mechanism of drug failure or poisoning in MRSA infection.Materials and methods: Mice were infected with three different doses of MRSA and the changes in CYP450 expression, cytokines, and oxidative stress markers were evaluated.Results: The administration of an attack dose of MRSA caused serious symptoms of infection and resulted in a 40% mortality rate in the mice. MRSA induced strong inflammation and oxidative stress in the mice, predominantly caused by significant increases in interleukin (IL)-1β, IL-4, IL-6, macrophage inflammatory protein, glutathione S-transferase (GST), and malondialdehyde, and decreases in oxygen radical absorbance capacity and glutathione levels in the liver. The expression of IL-2, tumor necrosis factor-α, and GST was briefly suppressed, but increased on days 3 and 7. The increased inflammation and oxidative stress further induced a significant decrease in the mRNA levels and activities of CYP450 1A2, 2D22, 2E1, and 3A1 in MRSA-infected mice within the first day of infection.Conclusion: These results show that MRSA infection leads to inflammation and oxidative stress, and reduces the expression levels and activities of drug metabolism enzymes, which decreased drug metabolism in patients infected with MRSA. Therefore, to avoid a drug overdose, the plasma concentration of patients with MRSA infection should be continuously monitored.

Bacterial-targeting liposomes for synergistic nitric oxide/methicillin therapy in MRSA-infected osteomyelitis

Kai Lv,Zhen Wang,Wenjun He,Zijing Feng,Hui Xing,Yuanfang Jiang,Yingtong Lu,Jingjie Shang,Bin Guo,Hao Xu,Guowei Li,Bo Ning,Dong Ma

Nitric oxide (NO) as a promising therapeutic molecule for infection treatments is impeded by challenges of precise delivery and accumulation in treating deep tissue infections, such as osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA). Herein, a bacterial-targeting liposome (MN@Mal-Lips) assembled by maltotriose (Mal)-modified cholesterol and lecithin was presented for synergistic NO/methicillin (MET) therapy of MRSA-infected osteomyelitis. MN@Mal-Lips were specifically internalized by MRSA via Mal transporters and thus targetedly accumulated at deep MRSA-infected site. Attributed to the capabilities of NO to induce biofilm dispersal and reverse bacterial resistance, the precisely delivered NO combined with MET facilitating efficient bacterial eradication by disrupting bacterial cell membrane and damaging bacterial DNA. Furthermore, MN@Mal-Lips relieved the local inflammation by potentiating the polarization of macrophages to M2-type while suppressing the M1-type. Meanwhile, MN@Mal-Lips promoted the proliferation, migration, and mineralization of osteoblast, as well as upregulated osteogenesis-related genes, thus repairing the bone tissue. Together, this bacterial-targeting NO-delivery liposome system offers an effective therapeutic strategy for clinical management of MRSA-induced osteomyelitis and may provide great possibilities in the development of NO therapy combating with deep tissue infections caused by drug-resistant bacteria.

Cascade-driven nanomotors promote diabetic wound healing by eradicating MRSA biofilm infection

Jia Zheng,Yuanyuan Deng,Senfeng Zhao,Longhai Liu,Wei Wang,Jiawei Li,Wansong Chen,Liu Deng,Jianghua Li,You-Nian Liu

Bacterial infection, hypoxia, and inflammatory stress responses are the key obstacles that delay the healing of diabetic ulcers. Herein, DMSNs-Pt-LOX@Nisin (DPLN) nanomotors that exhibits cascade propulsion and can specifically target methicillin-resistant Staphylococcus aureus (MRSA) is developed. The DPLN can facilitate the conversion of the abundant lactic acid existed in diabetic wounds, resulting in the generation of hydrogen peroxide (H 2 O 2 ). Meanwhile, the unilateral Pt nanodendrites (Pt DNs) catalyze H 2 O 2 to produce O 2 , driving the nanomotors to rapidly penetrate into the biofilm. Moreover, by loading Nisin, which can bind to lipid II of Gram-positive bacteria, the nanomotors can target MRSA through a self-driven process. Both in vitro and in vivo experiments demonstrate that the nanomotors can eradicate MRSA biofilms. Furthermore, animal studies show that DPLN are able to expedite the process of wound healing in diabetic mice through the eradication of biofilms, facilitation of angiogenesis, and mitigation of inflammation. These novel nanomotors combining cascade propulsion and MRSA targeting represent an encouraging and potentially effective approach in diabetic ulcer treatment.

A biomimetic nano-NET strategy for the treatment of MRSA-related implant-associated infection

Huan Xu,Dengwei He,Huimin Tao

Methicillin-resistant Staphylococcus aureus (MRSA) has spread across diverse global environments, and MRSA-related infection is a major threat to public health. Implant-associated infection (IAI) caused by MRSA remains a tough global clinical problem. Conventional antibiotic therapy has limited efficacy in treating MRSA-related IAI, and antibiotic abuse has resulted in the emergence of multidrug-resistant bacteria. Hence, there is a necessity to explore more effective approaches to deal with MRSA-related IAI. Herein, inspired by neutrophil extracellular traps (NETs) released by neutrophils to kill microorganisms, this study proposes a novel biomimetic nano-NET strategy using an epsilon-poly- l -lysine-coated CuO 2 nanoplatform, denoted as PCPNAs. The function-adaptive nanoplatform exhibited excellent Fenton-like performance, including robust ROS generation and GSH scavenging ability. PCPNAs showed >90% cell viability in mammalian cells and reduced bacterial burden by 7.65 log 10 CFU in vitro . Moreover, the positively charged PCPNAs could easily bind to negatively charged MRSA cells through charge-coupling and simultaneously exerted a trapping effect on MRSA cells. Notably, PCPNAs self-assembled into web-like structures to physically trap and kill biofilm bacteria, achieving 99.58% biofilm eradication. Furthermore, PCPNAs showed satisfactory biocompatibility in vivo and displayed ideal anti-bacterial and anti-inflammatory effects in a mouse model with implant-associated infection. With further development and optimization, the biomimetic nano-NET strategy based on PCPNAs provides a new therapeutic option for the treatment of MRSA-related implant-associated infection. Schematic of a biomimetic nano-NET strategy based on PCPNAs for the treatment of MRSA-related implant-associated infections.

Multifunctional hydrogel with mild photothermal properties enhances diabetic wound repair by targeting MRSA energy metabolism

Gao Qian,Hu Fangfang,Chai Zihan,Zheng Caiyun,Zhang Wenhui,Pu Ke,Yang Ziyi,Zhang Yanni,Ramrkrishna Seeram,Wu Xianglong,Lu Tingli

Background Diabetic wound infections, exacerbated by multidrug-resistant pathogens like MRSA, remain a critical challenge due to biofilm persistence and dysregulated oxidative-inflammatory-metabolic crosstalk. Results In this work, we engineered COG-Z@P200 hydrogel, a chitosan-based hydrogel integrating polydopamine-coated ZIF-8 nanoparticles, to synergize mild photothermal therapy (40–45 °C) with metabolic-immune reprogramming. Upon NIR irradiation, COG-Z@P200 disrupted MRSA through Zn 2 ⁺-mediated membrane destabilization and localized hyperthermia, achieving >99.5% eradication via combined physical puncture and metabolic interference. Multi-omics analyses revealed suppression of glycolysis (eno, gap downregulation), TCA cycle arrested (s ucC, sdhA, icd inhibition), and disruption of arginine biosynthesis ( arcA , arcC , arcD downregulation), impairing biofilm formation and pathogenicity. Concurrent silencing of quorum sensing and virulence genes ( agr, sec, lac, opp, sdrD ) further destabilized MRSA, while upregulation of stress-response genes ( yidD, nfsA, kdpA ) indicated bacterial metabolic paralysis. In diabetic murine models, the hydrogel attenuated oxidative stress (DHE-confirmed ROS reduction), polarized macrophages to pro-healing M2 phenotypes (Arg-1⁺/TNF-α↓), and enhanced angiogenesis (VEGF/CD31↑) alongside aligned collagen deposition. This multifunctional action accelerated wound closure by 48% versus controls, outperforming clinical standards. By converging nanomaterial-enabled bactericidal strategies with host microenvironment recalibration, COG-Z@P200 hydrogel redefined diabetic wound management, offering an antibiotic-free solution against multidrug-resistant infections. Conclusion Our work established a biomaterial paradigm that concurrently targets pathogen vulnerabilities and restores tissue homeostasis, addressing the multidimensional complexity of chronic wounds. Graphical abstract

Colorimetric and fluorescent dual-identification of Methicillin-Resistant Staphylococcus aureus (MRSA) using programmable CRISPR/Cas12a system

Xianfeng Wang,Chengxiang Chu,Yuanyi Deng,Yi Ma,Mei Yang,Huibo Luo,Danqun Huo,Changjun Hou

Accurate identification of Staphylococcus aureus ( S. aureus ) is crucial for food safety and clinical diagnosis. Particularly, identifying drug-resistant strains guides effective treatment and prevention of infectious diseases. Herein, we presented a highly efficient programmable CRISPR/Cas12a system for identification of methicillin-resistant S. aureus (MRSA). Genus-specific gene (spec gene) and methicillin-resistant gene (mecA gene) of S. aureus were amplified by PCR. According to the sequences of spec gene and mecA gene, corresponding programmable crRNAs were designed and prepared to construct CRISPR/Cas12a system, which recognized and bound to the PCR products through complementary interactions to activate the trans -cleavage activity of Cas12a. This led to the indiscriminate digestion of surrounding FQ-reporter, releasing a distinct fluorescence signal for MRSA identification. In addition, we devised a pair of AuNPs-DNA probes for colorimetric recognition of S. aureus . Target-triggered trans -cleavage for linker probe led to an non-aggregation of AuNPs-DNA probes pair. This led to a noticeable appearance of red color, enabling naked-eye detection. Thus, MRSA identification was realized with remarkable sensitivity and exceptional selectivity. Successful identification of MRSA in clinical samples validated the practical applications of the proposed CRISPR/Cas12a assay, establishing it as a universal platform for diagnosing pathogenic microorganisms with versatility and compatibility.

Synthesis of substituted tryptanthrin via aryl halides and amines as antitumor and anti-MRSA agents

Xudong Zheng,Baolong Hou,Rui Wang,Yinyin Wang,Cuiling Wang,Huan Chen,Li Liu,Jilin Wang,Xiumei Ma,Jianli Liu

The natural alkaloid, tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione), and its analogues are found to exhibit potent antitumor and anti -MRSA activities. An efficient and convenient method has been developed for the synthesis of tryptanthrin D-ring derivatives through the reaction of substituted tryptanthrins and secondary amines in moderate to good yields. Some of the new compounds exhibited antitumor activities against the human tumor cell lines A549, HCT116 and MDA-MB-231, with mean IC 50 values at low micromolar levels. In addition, some of the compounds showed excellent anti -MRSA activities and were more effective than vancomycin , with MIC values of 0.31–1.25 μg/mL for Mu50,RN4220, and Newman strains.

Inhibitory Effect of Non-Saccharomyces Starmerella bacillaris CC-PT4 Isolated from Grape on MRSA Growth and Biofilm

Shen Yong,Bai Xue,Wang Jiaxi,Zhou Xiran,Meng Rizeng,Guo Na

Methicillin-resistant Staphylococcus aureus (MRSA) is a notorious pathogen with biofilm-forming and drug-resistant properties that make it difficult to eradicate. In this study, the inhibition of MRSA (ATCC 43300) by Starmerella bacillaris CC-PT4 (CGMCC No. 23573) was evaluated. The results showed that the inhibition of MRSA growth and biofilm was caused by S. bacillaris CC-PT4 cell-free supernatant (CFS). The CFS of S. bacillaris CC PT4 at different times can effectively inhibit the formation of MRSA biofilm, remove the preformed biofilm, and down-regulate the related genes that promote the formation of biofilm. Afterwards, untargeted metabolomics was performed to analyze the CFS of S. bacillaris CC-PT4. Several molecules with antibacterial and inhibitory biofilm effects from the CFS were found, one of which, 2-amino-1-phenylethanol (APE), has not been reported to have antiMRSA ability before. In this study, molecular docking analysis and in vitro experiments were used to verify the function of APE to inhibit MRSA. These results indicate that S. bacillaris CC-PT4 CFS can effectively inhibit MRSA which has potential application value in controlling MRSA.

Butyrate protects against MRSA pneumonia via regulating gut-lung microbiota and alveolar macrophage M2 polarization

Yan Zhao,Haoming Sun,Yiwei Chen,Qiang Niu,Yiting Dong,Mei Li,Ye Yuan,Xiaojun Yang,Qingzhu Sun

Novel multifunctional dual-dynamic-bonds crosslinked hydrogels for multi-strategy therapy of MRSA-infected wounds

Pengpeng Deng,Xiao Liang,Feixiang Chen,Yun Chen,Jinping Zhou

Wound healing is a complex dynamic process involving hemostasis, inflammation, proliferation and remodeling stages. It is urgent need to develop multifunctional hydrogels to treat multiple links of wound healing. In this work, we designed novel multifunctional dual-dynamic-bonds crosslinked hydrogels through the electrostatic interaction between phenylboric acid and the amino group of chitosan, and the dynamic borate ester bond between phenylboric acid and the catechol structure of PDA-modified CNTs. This dual dynamic cross-linking mechanism endowed hydrogels with very fast self-healing properties, which could quickly form a whole dressing after being injected into the wound site. The phenylboric acid and catechol structures endowed hydrogels with excellent adhesion properties, the adhesion strength to pig skin was up to 27.6 kPa, could be used for hemostasis in vivo . Moreover, hydrogels displayed the advantages of injectable, rapid shape adaptation, antioxidant, biocompatibility, blood compatibility, electrical conductivity and photothermal antibacterial properties. In the MRSA-infected wound model, hydrogels could effectively reduce the expression level of wound inflammatory factors, accelerate collagen deposition, epithelial tissue and vascular regeneration, and thus promote wound healing. This work provides a new idea for the design of multi-strategy therapy for wound healing and has broad clinical application prospects.

Assessment of anti-MRSA activity of auranofin and florfenicol combination: a PK/PD analysis

Li Jian-Guo,Zhang Chuan-Jian,Liang Liu-Yan,Lu Ting-Yin,Zhong Long-Gen,Zhong Wei-Cheng,Niu Chao-Yan,Sun Jian,Liao Xiao-Ping,Zhou Yu-Feng

AimsMethicillin-resistant Staphylococcus aureus (MRSA) is an important zoonotic pathogen with multidrug-resistant phenotypes increasingly prevalent in both human and veterinary clinics. This study evaluated the potential of auranofin (AF) as an antibiotic adjuvant to enhance the anti-MRSA activity of florfenicol (FFC) and established a pharmacokinetic/pharmacodynamic (PK/PD) model to compare the efficacy of FFC alone or in combination with AF against MRSA.Methods and resultsWe observed an increased susceptibility and significant synergistic effects of MRSA to FFC in the presence of AF. The combination treatment of FFC and AF significantly inhibited MRSA biofilm formation and decreased the metabolic activity of mature biofilms. Importantly, AF fully restored the efficacy of FFC in both Galleria mellonella larvae and murine models. PK/PD studies demonstrated that the AUC24h/MIC targets required to achieve the bacteriostatic and bactericidal effects were significantly lower with the combination therapy compared to florfenicol monotherapy.ConclusionsThese results reveal the potential of AF as a novel adjuvant to improve the efficacy of FFC in treating MRSA invasive infections and provide valuable PK/PD insights for designing effective combination therapies.

Self-assembled gallic acid-rare earth nanocomplexes against MRSA with multi-targeting antibacterial mechanisms robustly combating bacterial resistance

Xian Liu,Qiwu Yuan,Yang Yang,Ke Li,Nanjiong Pang,Jiangtao Wang,Ming Yang,Xia Li,Junling Guo,Xuepin Liao,Bi Shi

Antibiotic resistance poses a significant threat to global public health, urgently demanding the development of new antibacterial agents with high efficacy and low resistance potential. In this study, we engineered self-assembled nanocomplexes of the gallic acid (GA) with rare earth (Re) ions (Ce 3+ , Gd 3+ , and Yb 3+ ), leveraging the unique multidentate structures of polyphenols to enhance antibacterial performance while minimizing resistance. These GA-Re nanocomplexes demonstrated potent activity against both antibiotic-sensitive Staphylococcus aureus (ASSA) and methicillin-resistant S. aureus (MRSA), with minimum inhibitory concentrations as low as 0.5 mmol/L. Viable MRSA cell numbers decreased from 7.40 × 10 7 CFU/mL to 8.43 × 10 6 and 7.33 × 10 2 CFU/mL when treated with penicillin (PEN) and GA-Gd for 24 h, respectively, indicating higher bactericidal efficiency of GA-Gd. Remarkably, no resistance developed in ASSA even after 60 days(d) of continuous exposure to GA-Gd, in contrast to the significant resistance observed with PEN (1024-fold) and neomycin (256-fold) after 28 d. The multidentate structure of GA facilitated versatile interactions with bacterial surface structures, enabling multiple mechanisms of action targeting cell walls, membranes, DNA, and cellular metabolism. Moreover, in vivo studies revealed that GA-Gd was effectively metabolized and excreted without accumulation or toxicity, and also accelerates the healing of MRSA infected wounds. These findings suggest the potential of self-assembled Re-based phenolic nanocomplexes as promising candidates for combating antibiotic-resistant bacterial infections, and pave the way for next-generation antibacterial agents.