Combination antimicrobial therapy to manage resistance
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PROVIDER: S-EPMC10287501 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Antimicrobial resistance (AMR) poses a significant global health threat, rendering many infections untreatable. To combat AMR, repurposing approved drugs has emerged as a cost-effective strategy. Bismuth drugs, when combined with antibiotics, have been proven to be effective against Helicobacter pylori, including antibiotic-resistant strains. However, bismuth drugs alone exhibit limited antimicrobial activity against a narrow spectrum of pathogens. Therefore, a novel approach to enhance the efficacy and broaden the antimicrobial spectrum of bismuth drugs is highly desirable. Herein, we show that a naturally occurring monoterpenoid, hinokitiol, could potentiate the antimicrobial activity of bismuth drugs. We demonstrate a strong synergy between hinokitiol and colloidal bismuth subcitrate (CBS) against various Gram-positive and Gram-negative bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA). Moreover, the combination of hinokitiol and CBS exhibits anti-biofilm activity by preventing biofilm formation and eliminating S. aureus persister cells. Importantly, the combination therapy demonstrates promising antimicrobial efficacy in murine infection models including skin wound, gastrointestinal and blood infections. Mechanistic studies reveal that hinokitiol enhances bismuth ion (Bi(iii)) accumulation and reduces intracellular iron levels. By using thermal proteome profiling combined with dynamic quantitative proteomics analysis, we demonstrate that the bismuth-hinokitiol combination propagated the bismuth binding and interfered with ribosome synthesis, the glycolysis process, impaired bacterial cell wall synthesis and pathogenesis in MRSA. Our finding highlights the potential of combinatorial hinokitiol and bismuth drugs in the fight against AMR.
| S-EPMC11865920 | biostudies-literature
Project description:BackgroundNovel diagnostics are needed to manage antimicrobial resistance (AMR). Patient preferences are important in determining whether diagnostic tests are successful in practice, but there are few data describing the test attributes which matter most to patients. We elicited patients' preferences for attributes of diagnostic tests that could be used to reduce unnecessary antibiotic use in primary care across seven European countries.MethodsWe used an online stated preference survey, including a discrete choice experiment (DCE). The DCE explored how patients make trade-offs between three key attributes of diagnostic tests: the speed that results were available, confidence in the test results, and how convenient it is to take the test. Individuals were eligible to complete the survey if they had taken antibiotics within the last 2 years and were resident in Germany, Italy, Spain, France, Greece, the Netherlands or the United Kingdom (UK).ResultsIn total, 988 respondents completed the survey. The DCE responses illustrated that speed was the least important attribute in most countries. Responses from Germany and the Netherlands indicated that confidence was most important in these countries. Responses from the UK, France, Spain and Italy showed convenience as the most important attribute in these countries. Two attributes, confidence and convenience, were jointly favoured by respondents in Greece.ConclusionPatients in different European countries do not have the same preferences for the attributes of diagnostic tests to manage AMR in primary care. Failure to account for such differences during test development could reduce test uptake, result in continued overuse of antibiotics, and hamper marketisation.
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Project description:Background: Current standard of care (SOC) regimens against nontuberculous mycobacteria (NTM) usually result in unsatisfactory therapeutic responses, primarily due to multi-drug resistance and antibiotic susceptibility-guided therapies. In the midst of rising incidences in NTM infections, strategies to develop NTM-specific treatments have been explored and validated. Methods: To provide an alternative approach to address NTM-specific treatment, IDentif.AI was harnessed to rapidly optimize and design effective combination therapy regimens against Mycobacterium abscessus (M. abscessus), the highly resistant and rapid growth species of NTM. IDentif.AI interrogated the drug interaction space from a pool of 6 antibiotics, and pinpointed multiple clinically actionable drug combinations. IDentif.AI-pinpointed actionable combinations were experimentally validated and their interactions were assessed using Bliss independence model and diagonal measurement of n-way drug interactions. Results: Notably, IDentfi.AI-designed 3- and 4-drug combinations demonstrated greater %Inhibition efficacy than the SOC regimens. The platform also pinpointed two unique drug interactions (Levofloxacin (LVX)/Rifabutin (RFB) and LVX/Meropenem (MEM)) that may serve as the backbone of potential 3- and 4-drug combinations like LVX/MEM/RFB, which exhibited 58.33±4.99 %Inhibition efficacy against M. abscessus. Further analysis of LVX/RFB via Bliss independence model pointed to dose-dependent synergistic interactions in clinically actionable concentrations. Conclusions: IDentif.AI-designed combinations may provide alternative regimen options to current SOC combinations that are often administered with Amikacin, which has been known to induce ototoxicity in patients. Furthermore, IDentif.AI pinpointed 2-drug interactions may also serve as the backbone for the development of other effective 3- and 4-drug combination therapies. The findings in this study suggest that this platform may contribute to NTM-specific drug development.
| S-EPMC9576615 | biostudies-literature
Project description:This study involves mutagenizing C32, a melanoma cell line, with ENU to identify those mutations which engender resistance to a targeted treatment.
| EGAS00001001614 | EGA
Project description:Acquired resistance to combination dabrafenib/trametinib therapy in BRAF mutant metastatic melanoma
| PRJEB7503 | ENA
Project description:Intestinal infection with enterotoxigenic Escherichia coli (ETEC) is an important disease in swine resulting in significant economic losses. Knowledge about the epidemiology, the diagnostic approach and methods of control are of fundamental importance to tackle the disease. The ETEC causing neonatal colibacillosis mostly carry the fimbriae F4 (k88), F5 (k99), F6 (987P) or F41, while the ETEC of post-weaning diarrhoea carry the fimbriae F4 (k88) and F18. These fimbriae adhere to specific receptors on porcine intestinal brush border epithelial cells (enterocytes), starting the process of enteric infection. After this colonization, the bacteria produce one or more enterotoxins inducing diarrhoea, such as the heat stable toxin a (STa), the heat stable toxin b (STb), and the heat labile toxin (LT). A role in the pathogenesis of the disease was demonstrated for these toxins. The diagnosis of enteric colibacillosis is based on the isolation and quantification of the pathogenic E.coli coupled with the demonstration by PCR of the genes encoding for virulence factors (fimbriae and toxins). The diagnostic approach to enteric colibacillosis must consider the differential diagnosis and the potential different causes that can be involved in the outbreak. Among the different methods of control of colibacillosis, the use of antimicrobials is widely practiced and antibiotics are used in two main ways: as prophylactic or metaphylactic treatment to prevent disease and for therapeutic purposes to treat diseased pigs. An accurate diagnosis of enteric colibacillosis needs an appropriate sampling for the isolation and quantification of the ETEC responsible for the outbreak by using semi-quantitative bacteriology. Definitive diagnosis is based on the presence of characteristic lesions and results of bacteriology along with confirmation of appropriate virulence factors to identify the isolated E.coli. It is important to confirm the diagnosis and to perform antimicrobial sensitivity tests because antimicrobial sensitivity varies greatly among E. coli isolates. Growing concern on the increase of antimicrobial resistance force a more rational use of antibiotics and this can be achieved through a correct understanding of the issues related to antibiotic therapy and to the use of antibiotics by both practitioners and farmers.
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| S-EPMC4653986 | biostudies-literature
Project description:Combination chemotherapy has been a mainstay in cancer treatment for the last 60 years. Although the mechanisms of action and signaling pathways affected by most treatments with single antineoplastic agents might be relatively well understood, most combinations remain poorly understood. This review presents the most common alterations of signaling pathways in response to cytotoxic and targeted anticancer drug treatments, with a discussion of how the knowledge of signaling pathways might support and orient the development of innovative strategies for anticancer combination therapy. The ultimate goal is to highlight possible strategies of chemotherapy combinations based on the signaling pathways associated with the resistance mechanisms against anticancer drugs to maximize the selective induction of cancer cell death. We consider this review an extensive compilation of updated known information on chemotherapy resistance mechanisms to promote new combination therapies to be to discussed and tested.
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Project description:Successful cancer control relies on overcoming resistance to cell death and on activation of host antitumor immunity. Oncolytic viruses are particularly attractive in this regard, as they lyse infected tumor cells and trigger robust immune responses during the infection. However, repeated injections of the same virus promote antiviral rather than antitumor immunity and tumors may mount innate antiviral defenses to restrict oncolytic virus replication. In this article, we have explored if alternating the therapy virus could circumvent these problems. We demonstrate in two virus-resistant animal models a substantial delay in antiviral immune- and innate cellular response induction by alternating injections of two immunologically distinct oncolytic viruses, adenovirus, and vaccinia virus. Our results are in support of clinical development of heterologous adeno-/vaccinia virus therapy of cancer.
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Project description:Recent work has revealed essential epigenetic dependencies in many cancers. Based on the functional antagonism between BAF/SWI/SNF and Polycomb repressive complex 2 chromatin remodeling in SMARCB1-deficient sarcomas, we and colleagues recently completed the clinical trial of the EZH2 inhibitor tazemetostat, leading to its FDA approval. However, the principles of response and resistance to epigenetic therapy in general and tazemetostat in particular remain unknown. Using comparative functional genomics of clinical tumor specimens and diverse experimental model systems, we have now defined molecular mechanisms of resistance to tazemetostat in epithelioid sarcomas and rhabdoid tumors. We found distinct classes of acquired mutations that converge on the RB/E2F axis and decouple EZH2 inhibition-dependent tumor cell differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest, despite an active transcriptional response, and provides a general mechanism for effective EZH2 inhibitor therapy. Thus, we develop combination strategies to circumvent tazemetostat resistance by using cell cycle bypass and synthetic lethal targeting, and provide prospective biomarkers for future therapy stratification. This offers a paradigm for rational epigenetic combination therapy suitable for immediate translation to clinical trials for patients.
2023-02-07 | GSE213845 | GEO