Biology subjects

Lamers, R. P.

Publications and source records attributed to Lamers, R. P..

4 recordsLinked to original sources

bioRxiv2026

Matched Plasma and Tissue Proteomics Reveal the Selective Nature of Circulating Biomarkers of Human Aging

Aging is systemic, yet how circulating proteins reflect molecular aging within solid tissues remains unclear. We profiled 5,415 proteins using Olink Explore HT in 178 adults aged 20-87 years, including matched plasma-muscle (n = 56) and plasma-ovary (n = 24) pairs. Plasma-tissue concordance was limited, with 50 muscle and 17 ovarian proteins significantly correlated, indicating that plasma selectively reflects tissue protein abundance. Age-correlated proteins and pathways differed markedly across sex and tissue strata, Including immune/inflammatory signatures in female plasma, vascular and extracellular-matrix pathways in male plasma, and collagen remodeling in the ovary. Expression Variation Analysis further revealed predominantly context-specific age-related changes in protein coordination, including FAS/FADD/TRAIL death-receptor networks in plasma and a TP53-CDKN1A senescence-associated axis in muscle. Exploratory multivariate models identified additional plasma associations with subsets of tissue proteins, including tissue-restricted muscle proteins. Together, these findings define plasma as a selective, context-dependent window into human tissue aging.

systems biology↗

bioRxiv2023

Metabolic connections between folate and peptidoglycan pathways in Pseudomonas aeruginosa inform rational design of a dual-action inhibitor

Peptidoglycan is an important bacterial macromolecule that confers cell shape and structural integrity, and a key antibiotic target. The synthesis and turnover of peptidoglycan are carefully coordinated with other cellular processes and pathways. Although there are established connections between peptidoglycan and DNA replication or outer membrane biosynthesis, connections between peptidoglycan and folate metabolism are comparatively unexplored. Folate is an essential cofactor for bacterial growth and required for the synthesis of many important metabolites. Here we show that inhibition of folate synthesis in the important Gram-negative pathogen Pseudomonas aeruginosa has downstream effects on peptidoglycan metabolism and integrity. Folate inhibitors reduced expression of the AmpC {beta}-lactamase through perturbation of peptidoglycan recycling, potentiating the activity of {beta}-lactams normally cleaved by that resistance enzyme. Folate inhibitors also synergized with fosfomycin, which inhibits MurA - the first committed step in peptidoglycan synthesis - resulting in dose-dependent formation of round cells that underwent explosive lysis.The insights from this work were used to design a dual-active inhibitor that overcomes NDM-1-mediated meropenem resistance and synergizes with the folate inhibitor, trimethoprim. This work shows that folate and peptidoglycan metabolism are intimately connected and offers new opportunities to exploit this relationship in strategies to overcome antibiotic resistance in Gram-negative pathogens.

microbiology↗

bioRxiv2021

Hyperpiliation reduces Pseudomonas aeruginosa pathogenicity by impeding type III secretion

Type IVa pili (T4aP) are important virulence factors for many bacterial pathogens. Previous studies suggested that the retraction ATPase, PilT, modulates pathogenicity due to its critical role in pilus dynamics and twitching motility. Here we use a Caenorhabditis elegans slow killing model to show that hyperpiliation, not loss of pilus retraction, reduces virulence of Pseudomonas aeruginosa strains PAK and PA14 by interfering with function of the contact-dependent type III secretion system (T3SS). Hyperactivating point mutations in the P. aeruginosa PilSR two-component system that controls transcription of the major pilin gene, pilA, increased levels of surface pili to the same extent as deleting pilT, without impairing twitching motility. These functionally hyperpiliated PilSR mutants had significant defects in pathogenicity that were rescued by deleting pilA or by increasing the length of T3SS needles via deletion of the needle-length regulator, PscP. Hyperpiliated pilT deletion or pilO point mutants showed similar PilA-dependent impairments in virulence, validating the phenotype. Together, our data support a model where a surfeit of pili prevents effective engagement of contact-dependent virulence factors. These findings suggest that the role of T4aP retraction in virulence should be revised. SIGNIFICANCEPseudomonas aeruginosa is a major contributor to hospital-acquired infections and particularly problematic due to its intrinsic resistance to many front-line antibiotics. Strategies to combat this and other important pathogens include development of anti-virulence therapeutics. We show that the pathogenicity of P. aeruginosa is impaired when the amount of type IVa pili (T4aP) expressed on the cell surface increases, independent of the bacterias ability to twitch. We propose that having excess T4aP on the cell surface can physically interfere with productive engagement of the contact-dependent type III secretion toxin delivery system. A better understanding of how T4aP modulate interaction of bacteria with target cells will improve the design of therapeutics targeting components involved in regulation of T4aP expression and function, to reduce the clinical burden of P. aeruginosa and other T4aP-expressing bacteria.

microbiology↗

bioRxiv2016

The type IVa pilus machinery is pre-installed during cell division

Type IV pili (T4aP) are ubiquitous microbial appendages used for adherence, twitching motility, DNA uptake, and electron transfer. Many of these functions depend on dynamic assembly and disassembly of the pilus by a megadalton-sized, cell envelope-spanning protein complex located at the poles of rod-shaped bacteria. How the T4aP assembly complex becomes integrated into the cell envelope in the absence of dedicated peptidoglycan (PG) hydrolases is unknown. After ruling out potential involvement of housekeeping PG hydrolases in installation of the T4aP machinery in P. aeruginosa, we discovered that key components of inner (PilMNOP) and outer (PilQ) membrane subcomplexes are recruited to future sites of cell division. Mid-cell recruitment of a fluorescently tagged alignment subcomplex component, mCherry-PilO, depended on PilQ secretin monomers - specifically, their N-terminal PG-binding AMIN domains. PilP, which connects PilO to PilQ, was required for recruitment, while PilM, which is structurally similar to divisome component FtsA, was not. Recruitment preceded secretin oligomerization in the outer membrane, as loss of the PilQ pilotin, PilF, had no effect on localization. These results were confirmed in cells chemically blocked for cell division prior to outer membrane invagination. The hub protein FimV and a component of the Polar Organelle Coordinator complex - PocA - were independently required for mid-cell recruitment of PilO and PilQ. Together, these data reveal an integrated, energy-efficient strategy for the targeting and pre-installation - rather than retrofit - of the T4aP system into nascent poles, without the need for dedicated PG-remodelling enzymes.

microbiology↗