The Role of Hypermutation and Collateral Sensitivity in Antimicrobial Resistance Diversity ofPseudomonas aeruginosaPopulations in Cystic Fibrosis Lung Infection

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 15, 2023

Abstract Pseudomonas aeruginosa is an opportunistic pathogen which causes chronic, drug-resistant lung infections in cystic fibrosis (CF) patients. In this study, we explore the role of genomic diversification and evolutionary trade-offs antimicrobial resistance (AMR) diversity within P. populations sourced from CF infections. We analyzed 300 clinical isolates four patients (75 per patient), found that not a consistent indicator phenotypic AMR diversity. Remarkably, some genetically less diverse showed comparable to those with significantly more genetic variation. also observed hypermutator strains frequently exhibited increased sensitivity antimicrobials, contradicting expectations their treatment histories. Investigating potential trade-offs, no substantial evidence collateral among aminoglycoside, beta-lactam, or fluoroquinolone antibiotics, nor did observe between growth conditions mimicking sputum. Our findings suggest (i) prerequisite for diversity; (ii) may develop under selection pressure; (iii) prominent feature strains, (iv) single antibiotic does necessarily lead significant fitness costs. These insights challenge prevailing assumptions about evolution chronic infections, emphasizing complexity bacterial adaptation during infection. Importance Upon infection lung, rapidly acquires mutations, especially genes involved (AMR), often resulting diverse, treatment-resistant populations. However, population context still poorly understood. undergoing tobramycin evolved relative non-hypermutators same population. This finding suggests only exert weak pressure on lung. further these populations, suggesting be robust, naturally occurring phenomenon microbe. Preprint servers: manuscript has been submitted as preprint bioRxiv

Language: Английский

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A new type of AmpC β-lactamases defined by PIB-1, a metal-dependent carbapenem-hydrolyzing β-lactamase, fromPseudomonas aeruginosa: structural and functional analysis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 8, 2024

Abstract Antibiotic resistance is one of most important health concerns nowadays. β-lactamases are the determinants. Based on their structural and functional characteristics grouped in four categories. AmpC cephalosporinases presenting a set highly conserved residues. Here we crystallized PIB-1, Pseudomonas aeruginosa chromosomally-encoded β-lactamase. Its crystal structure shows it an β-lactamase, although number residues low. Functional analysis showed that PIB-1 able to degrade carbapenems but not typical substrate β-lactamases, cephalosporins. Besides, catalytic activity increases presence metal ions. Metals do bind active center increase degradation antibiotic. They induce formation trimers. This suggests oligomer more than monomer. While structurally low sequence conservation, profile its metal-dependence, prompts us position this enzyme as founder new group inside β-lactamases. Consequently, diversity might be wider expected.

Language: Английский

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Full factorial construction of synthetic microbial communities

Published: Sept. 30, 2024

Constructing combinatorially complete species assemblages is often necessary to dissect the complexity of microbial interactions and find optimal consortia. At moment, this accomplished through either painstaking, labor intensive liquid handling procedures, or use state-of-the-art microfluidic devices. Here we present a simple, rapid, low-cost, highly accessible methodology for assembling all possible combinations library strains, which can be implemented with basic laboratory equipment. To demonstrate usefulness methodology, construct set consortia from eight Pseudomonas aeruginosa empirically measure community-function landscape biomass productivity, identify highest yield community, that lead its function. This easy implement, inexpensive will make assembly easily laboratories.

Language: Английский

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Navigating collateral sensitivity: insights into the mechanisms and applications of antibiotic resistance trade-offs

Frontiers in Microbiology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 24, 2024

The swift rise of antibiotic resistance, coupled with limited new discovery, presents a significant hurdle to global public health, demanding innovative therapeutic solutions. Recently, collateral sensitivity (CS), the phenomenon in which resistance one increases vulnerability another, has come light as potential path forward this attempt. Targeting either unidirectional or reciprocal CS holds promise for constraining emergence drug and notably enhancing treatment outcomes. Typically, alteration bacterial physiology, such membrane potential, expression efflux pumps, cell wall structures, endogenous enzymatic actions, are involved evolved sensitivity. In review, we present thorough overview therapy, including its definition, importance, underlying mechanisms. We describe how can be exploited prevent enhance results treatment, but also discuss challenges restrictions that implementing practice. Our review underscores importance continued exploration mechanisms broad spectrum clinical validation approaches, offering insights into role valuable tool combating resistance.

Language: Английский

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Systematic mapping of antibiotic cross-resistance and collateral sensitivity with chemical genetics

Nature Microbiology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 2, 2024

Abstract By acquiring or evolving resistance to one antibiotic, bacteria can become cross-resistant a second which further limits therapeutic choices. In the opposite scenario, initial leads collateral sensitivity inform cycling combinatorial treatments. Despite their clinical relevance, our knowledge of both interactions is limited. We used published chemical genetics data Escherichia coli single-gene deletion library in 40 antibiotics and devised metric that discriminates between known cross-resistance collateral-sensitivity antibiotic interactions. Thereby we inferred 404 cases 267 collateral-sensitivity, expanding number by over threefold. validated 64/70 using experimental evolution. identifying mutants driving these genetics, demonstrated drug pair exhibit depending on mechanism. Finally, applied collateral-sensitive pairs combination reduce antibiotic-resistance development vitro.

Language: Английский

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