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Chemoproteomics with a Diaryliodonium Probe in Bacteria

ABSTRACT: The alarming increase in antimicrobial resistance (AMR) will soon limit treatment options for even routine infections, especially those caused by Gram-negative bacteria such as Acinetobacter baumannii. Here, we report a two-pronged approach to identify new vulnerabilities in such pathogens. Staring from diphenyleneiodonium (dPI) salts, which are compounds that have moderate antimicrobial activity against Gram-positive pathogens, we synthesized a focused heterocyclic library and report a new analogue that has much higher inhibitory potency against multidrug-resistant Acinetobacter baumannii and excellent efficacy in reduction of bacterial burden in a mouse neutropenic thigh infection model. The lead compound was also found to synergize with aminoglycosides, which are routinely used in the treatment of such infections in humans. Further, we synthesized an alkyne containing probe and using gel and mass spectrometry base chemoproteomics platforms, we identified proteins that have redox cofactors as putative targets for this class of compounds. Additionally, we also demonstrate that the modification of proteins is covalent and through a cysteine residue. Together, using complementary chemical biology approaches, new vulnerabilities in Gram-negative pathogens were identified that would help address a burgeoning global problem of AMR.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Acinetobacter Baumannii (strain Atcc 17978 / Cip 53.77 / Lmg 1025 / Ncdc Kc755 / 5377) Escherichia Coli

TISSUE(S): Cell Culture

SUBMITTER: Siddhesh Kamat

LAB HEAD: Siddhesh S. Kamat

PROVIDER: PXD033116 | Pride | 2023-03-29

REPOSITORIES: Pride

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			Action	DRS
	A_baumannii_Membrane_Replicate1.group	Other
	A_baumannii_Membrane_Replicate1.scan	Other
	A_baumannii_Membrane_Replicate1.wiff	Wiff
	A_baumannii_Membrane_Replicate1__FDR.xlsx	Xlsx
	A_baumannii_Membrane_Replicate2.group	Other

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Project description:<p>The study of antimicrobial resistance (AMR) in infectious diarrhea has generally been limited to cultivation, antimicrobial susceptibility testing and targeted PCR assays. When individual strains of significance are identified, whole genome shotgun (WGS) sequencing of important clones and clades is performed. Genes that encode resistance to antibiotics have been detected in environmental, insect, human and animal metagenomes and are known as "resistomes". While metagenomic datasets have been mined to characterize the healthy human gut resistome in the Human Microbiome Project and MetaHIT and in a Yanomani Amerindian cohort, directed metagenomic sequencing has not been used to examine the epidemiology of AMR. Especially in developing countries where sanitation is poor, diarrhea and enteric pathogens likely serve to disseminate antibiotic resistance elements of clinical significance. Unregulated use of antibiotics further exacerbates the problem by selection for acquisition of resistance. This is exemplified by recent reports of multiple antibiotic resistance in Shigella strains in India, in Escherichia coli in India and Pakistan, and in nontyphoidal Salmonella (NTS) in South-East Asia. We propose to use deep metagenomic sequencing and genome level assembly to study the epidemiology of AMR in stools of children suffering from diarrhea. Here the epidemiology component will be surveillance and analysis of the microbial composition (to the bacterial species/strain level where possible) and its constituent antimicrobial resistance genetic elements (such as plasmids, integrons, transposons and other mobile genetic elements, or MGEs) in samples from a cohort where diarrhea is prevalent and antibiotic exposure is endemic. The goal will be to assess whether consortia of specific mobile antimicrobial resistance elements associate with species/strains and whether their presence is enhanced or amplified in diarrheal microbiomes and in the presence of antibiotic exposure. This work could potentially identify clonal complexes of organisms and MGEs with enhanced resistance and the potential to transfer this resistance to other enteric pathogens.</p> <p>We have performed WGS, metagenomic assembly and gene/protein mapping to examine and characterize the types of AMR genes and transfer elements (transposons, integrons, bacteriophage, plasmids) and their distribution in bacterial species and strains assembled from DNA isolated from diarrheal and non-diarrheal stools. The samples were acquired from a cohort of pediatric patients and controls from Colombia, South America where antibiotic use is prevalent. As a control, the distribution and abundance of AMR genes can be compared to published studies where resistome gene lists from healthy cohort sequences were compiled. Our approach is more epidemiologic in nature, as we plan to identify and catalogue antimicrobial elements on MGEs capable of spread through a local population and further we will, where possible, link mobile antimicrobial resistance elements with specific strains within the population.</p>

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Chemoproteomics with a Diaryliodonium Probe in Bacteria

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