Providing insight into the mechanism of action of Cationic Lipidated Oligomers (CLOs) using metabolomics DOI Open Access
Maytham Hussein, Muhammad Bilal Hassan Mahboob, Jessica R. Tait

et al.

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

Published: Feb. 20, 2024

Abstract The increasing resistance of clinically relevant microbes against current commercially available antimicrobials underpins the urgent need for alternative and novel treatment strategies. Cationic lipidated oligomers (CLOs) are innovative alternatives to antimicrobial peptides, have reported potential. An understanding their mechanism action is required rationally design future strategies CLOs, either in monotherapy or synergistic combinations. In present study, metabolomics was used investigate potential metabolic pathways involved mechanisms antibacterial activity one CLO, C 12 -o-(BG-D)-10, which we previously shown be effective methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. metabolomes MRSA 43300 at 1, 3 6 h following with -o-(BG-D)-10 (48 µg/mL i.e., 3x MIC) were compared those untreated controls. Our findings reveal that studied disorganized bacterial membrane as first step towards its effect, evidenced by marked perturbations lipids peptidoglycan biosynthesis observed early time points h. Central carbon metabolism, DNA, RNA, arginine also vigorously perturbed, mainly points. Moreover, cells under osmotic oxidative stress across all points, evident trehalose pentose phosphate shunt. Overall, this study has, time, revealed may potentially stem from dysregulation multiple pathways. Importance Antimicrobial poses a significant challenge healthcare systems worldwide. Novel anti-infective therapeutics urgently needed combat drug-resistant microorganisms. show promise new agents Gram-positive pathogens like (MRSA). Understanding molecular mechanism(s) help CLO treatments along monotherapy. Here, describe killing CLOs MRSA. results our indicate had notable impact on organization cell envelope. inhibits arginine, histidine, central production, adding characteristics. This work illuminates unique opens an avenue oligomers/polymers clinical applications.

Language: Английский

The role of bacterial metabolism in antimicrobial resistance DOI
Mehrose Ahmad, Sai Varun Aduru, Robert P. Smith

et al.

Nature Reviews Microbiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Language: Английский

Citations

4
Advances in Antimicrobial Peptide Discovery via Machine Learning and Delivery via Nanotechnology DOI Creative Commons
Alexa Sowers, Guangshun Wang, Malcolm Xing

et al.

Microorganisms, Journal Year: 2023, Volume and Issue: 11(5), P. 1129 - 1129

Published: April 26, 2023

Antimicrobial peptides (AMPs) have been investigated for their potential use as an alternative to antibiotics due the increased demand new antimicrobial agents. AMPs, widely found in nature and obtained from microorganisms, a broad range of protection, allowing them be applied treatment infections caused by various pathogenic microorganisms. Since these are primarily cationic, they prefer anionic bacterial membranes electrostatic interactions. However, applications AMPs currently limited owing hemolytic activity, poor bioavailability, degradation proteolytic enzymes, high-cost production. To overcome limitations, nanotechnology has used improve AMP permeation across barriers, and/or protection against degradation. In addition, machine learning its time-saving cost-effective algorithms predict AMPs. There numerous databases available train models. this review, we focus on approaches delivery advances design via learning. The sources, classification, structures, mechanisms, role diseases, peptide engineering technologies, databases, techniques with minimal toxicity discussed detail.

Language: Английский

Citations

28
Uracil restores susceptibility of methicillin-resistant Staphylococcus aureus to aminoglycosides through metabolic reprogramming DOI Creative Commons

Lvyuan Fan,

Zhiyu Pan,

Xu Liao

et al.

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Jan. 24, 2023

Background: Methicillin-resistant Staphylococcus aureus (MRSA) has now become a major nosocomial pathogen bacteria and resistant to many antibiotics. Therefore, Development of novel approaches combat the disease is especially important. The present study aimed provide approach involving use nucleotide-mediated metabolic reprogramming tackle intractable methicillin-resistant S. infections. Objective: This aims explore bacterial effects mechanism uracil gentamicin in aureus. Methods: Antibiotic bactericidal assays was used determine synergistic effect gentamicin. How did regulate metabolism including tricarboxylic acid (TCA) cycle by GC-MS-based metabolomics. Next, genes activity key enzymes TCA cycle, PMF, intracellular aminoglycosides were measured. Finally, respiration, reactive oxygen species (ROS), ATP levels also assayed this study. Results: In study, we found that could synergize with kill MRSA (USA300) 400-fold. Reprogramming metabolomics displayed reprogrammed metabolism, enhanced elevate NADH production proton motive force, thereby promoting uptake Furthermore, increased cellular respiration production, resulting generation ROS. Thus, combined antibiotics induced death. Inhibition or ROS attenuate efficiency. Moreover, exhibited cooperation against other pathogenic bacteria. mouse mode infection, combination survival rate infected mice. Conclusion: Our results suggest enhances Gram-positive modulating metabolism.

Language: Английский

Citations

26
Metabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecks DOI Creative Commons
Paul Lubrano, Fabian Smollich, Thorben Schramm

et al.

Molecular Systems Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Language: Английский

Citations

1
Nutrient stress is a target for new antibiotics DOI
Lindsey A. Carfrae, Eric D. Brown

Trends in Microbiology, Journal Year: 2023, Volume and Issue: 31(6), P. 571 - 585

Published: Jan. 27, 2023

Language: Английский

Citations

19
Sub-inhibitory antibiotic treatment selects for enhanced metabolic efficiency DOI Creative Commons
Sai Varun Aduru, Karolina Szenkiel, Anika Rahman

et al.

Microbiology Spectrum, Journal Year: 2024, Volume and Issue: 12(2)

Published: Jan. 16, 2024

ABSTRACT Bacterial growth and metabolic rates are often closely related. However, under antibiotic selection, a paradox in this relationship arises: efficacy decreases when bacteria metabolically dormant, yet antibiotics select for resistant cells that grow fastest during treatment. That is, selection counterintuitively favors with fast but slow metabolism. Despite apparent contradiction, have historically been characterized primarily the context of growth, whereas extent analogous changes metabolism is comparatively unknown. Here, we observed previously evolved antibiotic-resistant strains exhibited unique between whereby nutrient utilization became more efficient, regardless rate. To better understand unexpected phenomenon, used simplified model to simulate bacterial populations adapting sub-inhibitory through successive bottlenecking events. Simulations predicted bactericidal concentrations could enhanced efficiency, defined based on utilization: drug-adapted able achieve same biomass while utilizing less substrate, even absence Moreover, simulations restoring efficiency would re-sensitize exhibiting metabolic-dependent resistance; confirmed result using adaptive laboratory evolutions Escherichia coli carbenicillin Overall, these results indicate direct selective pressure treatment differences evolutionary may determine both different corresponding re-sensitization approaches. IMPORTANCE The sustained emergence pathogens combined stalled drug discovery pipelines highlights critical need underlying evolution mechanisms resistance. end, related, exclusively growth. favor Through an integrated approach mathematical modeling experiments, study thereby addresses significant knowledge gap whether drives complement, and/or act independently, resistance phenotypes.

Language: Английский

Citations

8
Antibiotic-induced gut microbiota dysbiosis has a functional impact on purine metabolism DOI Creative Commons
Xin Liu,

Leyong Ke,

Ke Lei

et al.

BMC Microbiology, Journal Year: 2023, Volume and Issue: 23(1)

Published: July 13, 2023

Dysbiosis of the gut microbiota is closely linked to hyperuricemia. However, effect microbiome on uric acid (UA) metabolism remains unclear. This study aimed explore mechanisms through which microbiomes affect UA with hypothesis that modifying intestinal influences development hyperuricemia.We proposed combining an antibiotic strategy protein-protein interaction analysis test this hypothesis. The data demonstrated antibiotics altered composition as increased, and spectrum was connected purine salvage pathway. antibiotic-elevated concentration dependent increase in code for proteins involved metabolism, paralleled by depletion bacteria-coding enzymes required On contrary, abundant decreased We also found antibiotic-increased coincided a higher relative abundance bacteria hyperuricemia mice.An combined prediction bacterial function presents feasible method defining key Our investigations discovered core may be related enriches related-proteins. enrich salvage-proteins probiotic decreasing urate, are more likely killed antibiotics. Therefore, pathway potential target treatment both resistance.

Language: Английский

Citations

15
Mechanisms Underlying Synergistic Killing of Polymyxin B in Combination with Cannabidiol against Acinetobacter baumannii: A Metabolomic Study DOI Creative Commons
Maytham Hussein,

Rafah Allobawi,

Irini Levou

et al.

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(4), P. 786 - 786

Published: April 3, 2022

Polymyxins have resurged as the last-resort antibiotics against multidrug-resistant Acinetobacter baumannii. As reports of polymyxin resistance in A. baumannii with monotherapy become increasingly common, combination therapy is usually only remaining treatment option. A novel and effective strategy to combine polymyxins non-antibiotic drugs. This study aimed investigate, using untargeted metabolomics, mechanisms antibacterial killing synergy B a synthetic cannabidiol ATCC 19606. The panel Gram-negative pathogens (Acinetobacter baumannii, Klebsiella pneumoniae Pseudomonas aeruginosa) was also explored checkerboard static time-kill assays. B-cannabidiol showed synergistic activity assays both polymyxin-susceptible polymyxin-resistant isolates. metabolomics at 1 h demonstrated that (to greatest extent) significantly perturbed complex interrelated metabolic pathways involved bacterial cell envelope biogenesis (amino sugar nucleotide metabolism, peptidoglycan, lipopolysaccharide (LPS) biosynthesis), nucleotides (purine pyrimidine metabolism) peptide metabolism; notably, these are key regulators DNA RNA biosynthesis. Intriguingly, caused major perturbation membrane lipids (glycerophospholipids fatty acids) compared very minimal changes induced by monotherapies. At 4 h, more pronounced effects on abovementioned impact for first time disorganization formation, biosynthetic were most likely molecular combination. suggests possibility repositioning, polymyxins, MDR infections.

Language: Английский

Citations

20
Integration of text mining and biological network analysis: Identification of essential genes in sulfate-reducing bacteria DOI Creative Commons
Priya Saxena, Shailabh Rauniyar,

Payal Thakur

et al.

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: April 13, 2023

The growth and survival of an organism in a particular environment is highly depends on the certain indispensable genes, termed as essential genes. Sulfate-reducing bacteria (SRB) are obligate anaerobes which thrives sulfate reduction for its energy requirements. present study used Oleidesulfovibrio alaskensis G20 (OA G20) model SRB to categorize genes based their key metabolic pathways. Herein, we reported feedback loop framework gene interest discovery, from bio-problem set interest, leveraging expert annotation with computational prediction. Defined was applied retrieve literature databases (PubMed, PubMed Central) annotated them genome OA G20. Retrieved list further enrich protein-protein interaction corroborated pangenome analysis, enriched sets respective pathways under non-essential. Interestingly, sat (dde_2265) sulfur metabolism bridging between all Gene clusters involved were linked seleno-compound metabolism, amino acid secondary metabolite synthesis, cofactor biosynthesis. Furthermore, analysis demonstrated distribution, where 69.83% 116 mapped "persistent," inferring essentiality these Likewise, 21.55% involves specially formate dehydrogenases metallic hydrogenases, appeared "shell." Our methodology suggested that semi-automated text mining network may play crucial role deciphering previously unexplored mechanisms can help generate baseline prior perform any experimental studies.

Language: Английский

Citations

11
SERS Characterization of Filtrate Portions of Typhoid Blood Serum Samples Using 30 kDa Filtration Devices DOI Open Access

Maida Ehsan,

Muhammad Suleman Hassan, Haq Nawaz

et al.

Journal of Raman Spectroscopy, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

ABSTRACT Typhoid fever remains a significant global public health concern and continues to pose serious diagnostic challenges, particularly in the differentiation of different stages infection. In this study, surface‐enhanced Raman spectroscopy (SERS) combined with ultracentrifugation was explored design reliable method for characterization identification typhoid serum filtrate. During analysis samples by SERS, presence high molecular weight fractions (HMWF) occupying greater surface area masks low (LMWF). Therefore, HMWF removed from healthy samples, SERS employed biomolecular filtrate portions containing LMWF less than 30 kDa. Silver nanoparticles, as substrates, were used that enhanced signals biomolecules samples. The results show notable differences spectra two (control group) at 394, 648, 742, 771, 930, 1012, 1218, 1424, 1538 cm −1 . A chemometric tool, principal component (PCA), differentiate early‐ late‐stage each other control group. PCA highlighted spectral between diseased classified them separately proves ability has characterized differentiated effectively well individuals using blood proved offered noninvasive, rapid, cost‐effective disease detection progression study.

Language: Английский

Citations

0