Antimicrobial resistance of Pseudomonas aeruginosa: navigating clinical impacts, current resistance trends, and innovations in breaking therapies.

Pseudomonas aeruginosa, a Gram-negative bacterium, is recognized for its adaptability and opportunistic nature. It poses a substantial challenge in clinical settings due to its complicated antibiotic resistance mechanisms, biofilm formation, and capacity for persistent infections in both animal and human hosts. Recent studies revealed a potential zoonotic transmission of P. aeruginosa between animals, the environment, and human populations which highlights awareness of this microbe. Implementation of the One Health approach, which underscores the connection between human, animal, and environmental health, we aim to offer a comprehensive perspective on the current landscape of P. aeruginosa management. This review presents innovative strategies designed to counteract P. aeruginosa infections. Traditional antibiotics, while effective in many cases, are increasingly compromised by the development of multidrug-resistant strains. Non-antibiotic avenues, such as quorum sensing inhibition, phage therapy, and nanoparticle-based treatments, are emerging as promising alternatives. However, their clinical application encounters obstacles like cost, side effects, and safety concerns. Effectively addressing P. aeruginosa infections necessitates persistent research efforts, advancements in clinical development, and a comprehension of host-pathogen interactions to deal with this resilient pathogen.

Global genomic epidemiology of chromosomally mediated non-enzymatic carbapenem resistance in Acinetobacter baumannii: on the way to predict and modify resistance.

Introduction: Although carbapenemases are frequently reported in resistant A. baumannii clinical isolates, other chromosomally mediated elements of resistance that are considered essential are frequently underestimated. Having a wide substrate range, multidrug efflux pumps frequently underlie antibiotic treatment failure. Recognizing and exploiting variations in multidrug efflux pumps and penicillin-binding proteins (PBPs) is an essential approach in new antibiotic drug discovery and engineering to meet the growing challenge of multidrug-resistant Gram-negative bacteria. Methods: A total of 980 whole genome sequences of A. baumannii were analyzed. Nucleotide sequences for the genes studied were queried against a custom database of FASTA sequences using the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) system. The correlation between different variants and carbapenem Minimum Inhibitory Concentrations (MICs) was studied. PROVEAN and I-Mutant predictor suites were used to predict the effect of the studied amino acid substitutions on protein function and protein stability. Both PsiPred and FUpred were used for domain and secondary structure prediction. Phylogenetic reconstruction was performed using SANS serif and then visualized using iTOL and Phandango. Results: Exhibiting the highest detection rate, AdeB codes for an important efflux-pump structural protein. T48V, T584I, and P660Q were important variants identified in the AdeB-predicted multidrug efflux transporter pore domains. These can act as probable targets for designing new efflux-pump inhibitors. Each of AdeC Q239L and AdeS D167N can also act as probable targets for restoring carbapenem susceptibility. Membrane proteins appear to have lower predictive potential than efflux pump-related changes. OprB and OprD changes show a greater effect than OmpA, OmpW, Omp33, and CarO changes on carbapenem susceptibility. Functional and statistical evidence make the variants T636A and S382N at PBP1a good markers for imipenem susceptibility and potential important drug targets that can modify imipenem resistance. In addition, PBP3_370, PBP1a_T636A, and PBP1a_S382N may act as potential drug targets that can be exploited to counteract imipenem resistance. Conclusion: The study presents a comprehensive epidemiologic and statistical analysis of potential membrane proteins and efflux-pump variants related to carbapenem susceptibility in A. baumannii, shedding light on their clinical utility as diagnostic markers and treatment modification targets for more focused studies of candidate elements.

Phage Therapy, a Salvage Treatment for Multidrug-Resistant Bacteria Causing Infective Endocarditis.

Infective endocarditis (IE) is defined as an infection of the endocardium, or inner surface of the heart, most frequently affecting the heart valves or implanted cardiac devices. Despite its rarity, it has a high rate of morbidity and mortality. IE generally occurs when bacteria, fungi, or other germs from another part of the body, such as the mouth, spread through the bloodstream and attach to damaged areas in the heart. The epidemiology of IE has changed as a consequence of aging and the usage of implantable cardiac devices and heart valves. The right therapeutic routes must be assessed to lower complication and fatality rates, so this requires early clinical suspicion and a fast diagnosis. It is urgently necessary to create new and efficient medicines to combat multidrug-resistant bacterial (MDR) infections because of the increasing threat of antibiotic resistance on a worldwide scale. MDR bacteria that cause IE can be treated using phages rather than antibiotics to combat MDR bacterial strains. This review will illustrate how phage therapy began and how it is considered a powerful potential candidate for the treatment of MDR bacteria that cause IE. Furthermore, it gives a brief about all reported clinical trials that demonstrated the promising effect of phage therapy in combating resistant bacterial strains that cause IE and how it will become a hope in future medicine.

Pangenome analysis of Corynebacterium striatum: insights into a neglected multidrug-resistant pathogen.

BACKGROUND: Over the past two decades, Corynebacterium striatum has been increasingly isolated from clinical cultures with most isolates showing increased antimicrobial resistance (AMR) to last resort agents. Advances in the field of pan genomics would facilitate the understanding of the clinical significance of such bacterial species previously thought to be among commensals paving the way for identifying new drug targets and control strategies. METHODS: We constructed a pan-genome using 310 genome sequences of C. striatum. Pan-genome analysis was performed using three tools including Roary, PIRATE, and PEPPAN. AMR genes and virulence factors have been studied in relation to core genome phylogeny. Genomic Islands (GIs), Integrons, and Prophage regions have been explored in detail. RESULTS: The pan-genome ranges between a total of 5253-5857 genes with 2070 - 1899 core gene clusters. Some antimicrobial resistance genes have been identified in the core genome portion, but most of them were located in the dispensable genome. In addition, some well-known virulence factors described in pathogenic Corynebacterium species were located in the dispensable genome. A total of 115 phage species have been identified with only 44 intact prophage regions. CONCLUSION: This study presents a detailed comparative pangenome report of C. striatum. The species show a very slowly growing pangenome with relatively high number of genes in the core genome contributing to lower genomic variation. Prophage elements carrying AMR and virulence elements appear to be infrequent in the species. GIs appear to offer a prominent role in mobilizing antibiotic resistance genes in the species and integrons occur at a frequency of 50% in the species. Control strategies should be directed against virulence and resistance determinants carried on the core genome and those frequently occurring in the accessory genome.

Antimicrobial resistance and genotyping of Pseudomonas aeruginosa isolated from the ear canals of dogs in Japan.

The strong bond between dogs and their owners creates a close association that could result in the transfer of antibiotic-resistant bacteria from canines to humans, potentially leading to the spread of antimicrobial resistance genes. Pseudomonas aeruginosa, a common causative agent of persistent ear infections in dogs, is often resistant to multiple antibiotics. Assessing the antimicrobial resistance profile and genotype of P. aeruginosa is crucial for the appropriate use of veterinary pharmaceuticals. However, in recent years, few studies have been conducted on this bacterium in Japan. We determined the antimicrobial resistance profile and genotype of P. aeruginosa isolated from the ear canal of dogs in Japan in 2020. Analysis of antimicrobial resistance using disk diffusion tests indicated a high frequency of resistance to most antimicrobial agents. Particularly, 29 isolates from the ear canals of the 29 affected dogs (100%) were resistant to cefovecin, cefpodoxime, and florfenicol; however, they were susceptible to cefepime and piperacillin/tazobactam. Only 3.4, 10.3, and 10.3% of the isolates were resistant to ceftazidime, tobramycin, and gentamicin, respectively. Furthermore, upon analyzing the population structure using multilocus sequence typing, a considerably large clonal complex was not observed in the tested isolates. Three isolates, namely ST3881, ST1646, and ST532, were clonally related to the clinically isolated sequence types in Japan (such as ST1831, ST1413, ST1812, and ST1849), which is indicative of dog-to-human transmission. Considering the variation in antibiotic resistance compared to that reported by previous studies and the potential risk of dog-to-human transmission, we believe that the survey for antimicrobial resistance profile and population structure should be continued regularly. However, the prevalence of multidrug-resistant P. aeruginosa in dogs in Japan is not a crisis.

Mining metagenomes reveals diverse antibiotic biosynthetic genes in uncultured microbial communities.

Pathogens resistant to antimicrobials form a significant threat to public health worldwide. Tackling multidrug-resistant pathogens via screening metagenomic libraries has become a common approach for the discovery of new antibiotics from uncultured microorganisms. This study focuses on capturing nonribosomal peptide synthase (NRPS) gene clusters implicated in the synthesis of many natural compounds of industrial relevance. A NRPS PCR assay was used to screen 2976 Escherichia coli clones in a soil metagenomic library to target NRPS genes. DNA extracts from 4 clones were sequenced and subjected to bioinformatic analysis to identify NRPS domains, their phylogeny, and substrate specificity.Successfully, 17 NRPS-positive hits with a biosynthetic potential were identified. DNA sequencing and BLAST analysis confirmed that NRPS protein sequences shared similarities with members of the genus Delftia in the Proteobacteria taxonomic position. Multiple alignment and phylogenetic analysis demonstrated that clones no. 15cd35 and 15cd37 shared low bootstrap values (54%) and were distantly far from close phylogenetic neighbors. Additionally, NRPS domain substrate specificity has no hits with the known ones; hence, they are more likely to use different substrates to produce new diverse antimicrobials. Further analysis confirmed that the NRPS hits resemble several transposon elements from other bacterial taxa, confirming its diversity. We confirmed that the analyses of the soil metagenomic library revealed a diverse set of NRPS related to the genus Delftia. An in-depth understanding of those positive NRPS hits is a crucial step for genetic manipulation of NRPS, shedding light on alternative novel antimicrobial compounds that can be used in drug discovery and hence supports the pharmaceutical sector.

The predictive potential of different molecular markers linked to amikacin susceptibility phenotypes in Pseudomonas aeruginosa.

Informed antibiotic prescription offers a practical solution to antibiotic resistance problem. With the increasing affordability of different sequencing technologies, molecular-based resistance prediction would direct proper antibiotic selection and preserve available agents. Amikacin is a broad-spectrum aminoglycoside exhibiting higher clinical efficacy and less resistance rates in Ps. aeruginosa due to its structural nature and its ability to achieve higher serum concentrations at lower therapeutic doses. This study examines the predictive potential of molecular markers underlying amikacin susceptibility phenotypes in order to provide improved diagnostic panels. Using a predictive model, genes and variants underlying amikacin resistance have been statistically and functionally explored in a large comprehensive and diverse set of Ps. aeruginosa completely sequenced genomes. Different genes and variants have been examined for their predictive potential and functional correlation to amikacin susceptibility phenotypes. Three predictive sets of molecular markers have been identified and can be used in a complementary manner, offering promising molecular diagnostics. armR, nalC, nalD, mexR, mexZ, ampR, rmtD, nalDSer32Asn, fusA1Y552C, fusA1D588G, arnAA170T, and arnDG206C have been identified as the best amikacin resistance predictors in Ps. aeruginosa while faoAT385A, nuoGA890T, nuoGA574T, lptAT55A, lptAR62S, pstBR87C, gidBE126G, gidBQ28K, amgSE108Q, and rplYQ41L have been identified as the best amikacin susceptibility predictors. Combining different measures of predictive performance together with further functional analysis can help design new and more informative molecular diagnostic panels. This would greatly inform and direct point of care diagnosis and prescription, which would consequently preserve amikacin functionality and usefulness.