GmPcides: Componds that disarm antibiotic resistance in multiple gram-positive pathogens
GmPcides:解除多种革兰氏阳性病原体抗生素耐药性的化合物
基本信息
- 批准号:10577811
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:2-hydroxypyridineAddressAntibiotic ResistanceAntibiotic TherapyAntibioticsBacillus subtilisBacteriaBacterial InfectionsBiochemicalCause of DeathCell physiologyCellsCessation of lifeChemicalsClindamycinClinicalClostridium difficileCollaborationsCommunitiesDataDevelopmentDoseDrug DesignDrug resistanceEnvironmentErythromycinEssential GenesEvaluationExpression LibraryFamilyFibrinogenGenesGeneticGoalsGram-Positive BacteriaHealthcareHospitalsHumanIn VitroInfectionLeadMethodologyMicrobeMicrobial BiofilmsMicrobiologyModelingModificationMolecularMorbidity - disease rateMulti-Drug ResistanceMusNosocomial InfectionsOrganic ChemistryOrganismPathogenesisPathogenicityPatientsPositioning AttributePrevalenceProcessPropertyRecording of previous eventsResistanceRespiratory Tract InfectionsSkinSkin TissueSoft Tissue InfectionsSolubilityStreptococcus Group BStreptococcus pneumoniaeStreptococcus pyogenesStructureStructure-Activity RelationshipSystemTalentsTestingTissuesToxic effectTranslationsUrinary tractUrinary tract infectionUrineVancomycin resistant enterococcusantibiotic resistant infectionsbactericidecatheter associated UTIchemical geneticscombatdensitydrug resistant microorganismdruggable targetefficacy evaluationexperimental studyfitnessgenetic approachgenetic resourceglobal health emergencyimprovedin vitro Modelin vivoinnovationmethicillin resistant Staphylococcus aureusmortalitymouse modelmulti-drug resistant pathogennext generationnoveloverexpressionpathogenscaffoldsoft tissuestandard of caresynergismtherapeutic developmenttherapeutic target
项目摘要
PROJECT SUMMARY/ABSTRACT:
Hospital-Acquired Infections (HAI) have become a health care crisis and are a leading cause of death.
Further the hospital setting harbors a reservoir of lethal multidrug resistant (MDR) organisms, two million
patients suffer from HAI annually, resulting in 100,000 deaths and up to $4.5 billion in additional health care
expense. Thus, there is a global health emergency due to the growing prevalence of infections caused by MDR
HAI pathogens.
To combat these pathogens, we introduce GmPcides, a novel family of ring-fused 2-pyridone compounds
that are bactericidal against a broad spectrum of Gram-positive species, including all seven Gram-positive
species identified by the CDC as among the most significant antibiotic-resistant threats. These bacteria include
Clostridioides difficile, vancomycin-resistant Enterococci (VRE), methicillin-resistant Staphylococcus aureus
(MRSA), drug-resistant Streptococcus pneumoniae (S. pneumoniae), erythromycin-resistant Group A
Streptococcus (S. pyogenes) and clindamycin-resistant Group B Streptococcus (S. agalactiae). Significantly,
GmPcides are active against non-dividing bacteria and at sub-lethal doses, can disarm resistance, to re-
sensitize MDR microbes to antibiotic treatment, both in vitro and in vivo in a murine model of HAI infection to
standard-of-care antibiotics targeting multiple orthogonal processes. GmPcides have no effect on Gram-
negative viability or significant toxicity to host tissues. Our group developed GmPcides by combining the
talents of synthetic chemist Dr. Fredrik Almqvist with microbiologists Drs. Michael Caparon and Scott Hultgren
who propose to take advantage of their understanding of HAI pathogenesis and their unprecedented ability to
manipulate the substituent diversity of the 2-pyridone scaffold to address issues essential for the translation of
GmPcides, including: i) optimization of activity, stability and solubility through structure-activity relationship
(SAR) and structure-property relationship (SPR) studies; ii) Identification of the GmPcide target(s) using a
systems-level chemical-genetic approach and the comprehensive genetic resources available for the model
Gram-positive organism Bacillus subtilis; iii) optimization of activity against HAI bacteria growing in biofilm
communities; and iv) assessment of the in vivo efficacy of improved GmPcides in murine models of HAI
urinary tract and soft tissue infection. These experiments described here will lead to the identification of critical
druggable target(s) highly conserved among Gram-positive HAI pathogens and will lead to the development of
new antibiotic-sparing and antibiotic-disarming therapies to combat the challenge of MDR HAI Gram-positive
pathogens.
.
项目总结/文摘:
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael G. Caparon其他文献
Volatile profiling distinguishes emStreptococcus pyogenes/em from other respiratory streptococcal species
挥发性分析区分化脓性链球菌和其他呼吸道链球菌物种
- DOI:
10.1128/msphere.00194-23 - 发表时间:
2023-09-28 - 期刊:
- 影响因子:3.100
- 作者:
Amalia Z. Berna;Joseph A. Merriman;Leah Mellett;Danealle K. Parchment;Michael G. Caparon;Audrey R. Odom John;Jacqueline M. Achkar - 通讯作者:
Jacqueline M. Achkar
Streptococcus pyogenes protein F promotes invasion of HeLa cells.
化脓性链球菌蛋白 F 促进 HeLa 细胞的侵袭。
- DOI:
10.1099/00221287-144-11-3079 - 发表时间:
1998 - 期刊:
- 影响因子:1.5
- 作者:
Nobuhiko Okada;lchiro Tatsuno;Emanuel Hanski;Michael G. Caparon;C. Sasakawa - 通讯作者:
C. Sasakawa
Reprogramming aerobic metabolism mitigates Streptococcus pyogenes tissue damage in a mouse necrotizing skin infection model
在小鼠坏死性皮肤感染模型中,重新编程有氧代谢可减轻化脓性链球菌组织损伤。
- DOI:
10.1038/s41467-025-57348-x - 发表时间:
2025-03-15 - 期刊:
- 影响因子:15.700
- 作者:
Wei Xu;Tara R. Bradstreet;Zongsen Zou;Suzanne Hickerson;Yuan Zhou;Hongwu He;Brian T. Edelson;Michael G. Caparon - 通讯作者:
Michael G. Caparon
MP23-19 FIBRINOGEN DEPOSITS ON URINARY CATHETERS IN A TIME-DEPENDENT MATTER AND CO-LOCALIZES WITH <em>E. FAECALIS</em> IN PATIENTS WITH POSITIVE <em>E. FAECALIS</em> URINE CULTURES
- DOI:
10.1016/j.juro.2017.02.747 - 发表时间:
2017-04-01 - 期刊:
- 影响因子:
- 作者:
Tyler M. Bauman;Aaron M. Potretzke;Ana L. Flores-Mireles;Jennifer N. Walker;Alyssa M. Park;Henry L. Schreiber;Jerome S. Pinkner;Michael G. Caparon;Scott J. Hultgren;Alana Desai - 通讯作者:
Alana Desai
Michael G. Caparon的其他文献
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{{ truncateString('Michael G. Caparon', 18)}}的其他基金
Novel Therapeutic Approach to Invasive Group A Streptococcal Disease
侵袭性 A 组链球菌疾病的新治疗方法
- 批准号:
10452033 - 财政年份:2022
- 资助金额:
$ 39万 - 项目类别:
Novel Therapeutic Approach to Invasive Group A Streptococcal Disease
侵袭性 A 组链球菌疾病的新治疗方法
- 批准号:
10546470 - 财政年份:2022
- 资助金额:
$ 39万 - 项目类别:
Characterization of assembly factors for type IV secretion systems
IV 型分泌系统组装因子的表征
- 批准号:
10435561 - 财政年份:2021
- 资助金额:
$ 39万 - 项目类别:
GmPcides: Componds that disarm antibiotic resistance in multiple gram-positive pathogens
GmPcides:解除多种革兰氏阳性病原体抗生素耐药性的化合物
- 批准号:
10162829 - 财政年份:2021
- 资助金额:
$ 39万 - 项目类别:
GmPcides: Componds that disarm antibiotic resistance in multiple gram-positive pathogens
GmPcides:解除多种革兰氏阳性病原体抗生素耐药性的化合物
- 批准号:
10352471 - 财政年份:2021
- 资助金额:
$ 39万 - 项目类别:
Structure-function analysis of type IVB secretion systems
IVB型分泌系统的结构-功能分析
- 批准号:
10624264 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
EBPA-FIBROGEN INTERACTION IN ENTEROCOCCUS FAECALIS CAUTI
粪肠球菌中 EBPA-纤维原的相互作用
- 批准号:
9304949 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
EBPA-FIBROGEN INTERACTION IN ENTEROCOCCUS FAECALIS CAUTI
粪肠球菌中 EBPA-纤维原的相互作用
- 批准号:
8759401 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
EBPA-FIBROGEN INTERACTION IN ENTEROCOCCUS FAECALIS CAUTI
粪肠球菌中 EBPA-纤维原的相互作用
- 批准号:
8901925 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
CATABOLITE REPRESSION CONTROLS VIRULENCE IN STREPTOCOCCUS PYOGENES
分解代谢物抑制控制化脓性链球菌的毒力
- 批准号:
9174072 - 财政年份:2007
- 资助金额:
$ 39万 - 项目类别:
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