Rapid Development Of Resistance Research Articles

How to treat severe Acinetobacter baumannii infections.

To update the management of severe Acinetobacter baumannii infections (ABI), particularly those caused by multi-resistant isolates. The in vitro activity of the various antimicrobial agents potentially helpful in treating ABI is highly variable and has progressively decreased for many of them, limiting current therapeutic options. The combination of more than one drug is still advisable in most circumstances. Ideally, two active first-line drugs should be used. Alternatively, a first-line and a second-line drug and, if this is not possible, two or more second-line drugs in combination. The emergence of new agents such as Cefiderocol, the combination of Sulbactam and Durlobactam, and the new Tetracyclines offer therapeutic options that need to be supported by clinical evidence. The apparent limitations in treating infections caused by this bacterium, the rapid development of resistance, and the serious underlying situation in most cases invite the search for alternatives to antibiotic treatment, the most promising of which seems to be bacteriophage therapy.

Targeting the Metabolic Enzyme PGAM2 Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting BCL2 Signaling.

PGAM2 promotes resistance to enzalutamide by activating antiapoptotic BCL-xL and suppressing apoptosis, indicating that PGAM2 is a potential target for overcoming enzalutamide resistance in prostate cancer.

Discovery of Novel Thiazolyl Anthranilic Diamide Derivatives as Insecticidal Candidates.

Agricultural pests have caused huge losses in agricultural production and threaten global food security. Synthetic insecticides remain the major control method. However, with the rapid development of pest resistance and the increasingly stringent regulations on pesticide usage, the development of efficient insecticides with novel structures is particularly urgent. 26 novel anthranilic diamide derivatives containing thiazole moiety were designed based on the scaffold hopping strategy. Bioassay results indicated that compound 6e exhibited excellent insecticidal activity against a susceptible strain of diamondback moth (Plutella xylostella) with the median lethal concentration (LC50 ) being 0.65 mg/L, which was similar to chlorantraniliprole (LC50 = 0.53 mg/L). When treated on larvae of Plutella xylostella that were chlorantraniliprole-resistant, compound 6e showed marginally lower insecticidal activity than chlorantraniliprole (LC50 = 50.45 mg/L and 31.98 mg/L, respectively), suggesting a cross-resistance of compound 6e with chlorantraniliprole (resistance ratios, 77.6-fold and 60.3-fold, respectively). Compound 6e also showed good insecticidal activity against fall armyworm and beet armyworm with the mortalities of pests being 74% and 64%, respectively, at the concentration of 5 mg/L. In addition, compounds 6e and 12a showed delayed toxicity against red imported fire ant with mortality rates being 84% and 85% after 5 days of treatment at 1.0 mg/L, which was superior to chlorantraniliprole. The introduction of thiazole into anthranilic diamide scaffolds resulted in insecticidal leads 6e and 12a with excellent insecticidal activities and potential application in controlling red imported fire ants. The work also guides the discovery of insecticidal molecules with thiazole-containing anthranilic diamide scaffold. This article is protected by copyright. All rights reserved.

Overcoming Mycobacterium tuberculosis Drug Resistance: Novel Medications and Repositioning Strategies.

Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, is a global health concern, affecting millions worldwide. This bacterium has earned a reputation as a formidable adversary due to its multidrug-resistant nature, allowing it to withstand many antibiotics. The development of this drug resistance in Mycobacterium tuberculosis is attributed to innate and acquired mechanisms. In the past, rifampin was considered a potent medication for treating tuberculosis infections. However, the rapid development of resistance to this drug by the bacterium underscores the pressing need for new therapeutic agents. Fortunately, several other medications previously overlooked for tuberculosis treatment are already available in the market. Moreover, several innovative drugs are under clinical investigation, offering hope for more effective treatments. To enhance the effectiveness of these drugs, it is recommended that researchers concentrate on identifying unique target sites within the bacterium during the drug development process. This strategy could potentially circumvent the issues presented by Mycobacterium drug resistance. This review primarily focuses on the characteristics of novel drug resistance mechanisms in Mycobacterium tuberculosis. It also discusses potential medications being repositioned or sourced from novel origins. The ultimate objective of this review is to discover efficacious treatments for tuberculosis that can successfully tackle the hurdles posed by Mycobacterium drug resistance.

Azole potentiation in Candida species.

Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk populations and the rapid development of drug resistance and tolerance contributes to their clinical persistence. Few antifungal drugs are available, and their efficacy is declining due to the environmental overuse and the expansion of multidrug-resistant species. One way to prolong their utility is by applying them in combination therapy. Here, we highlight recently described azole potentiators belonging to different categories: natural, repurposed, or novel compounds. We showcase examples of molecules and discuss their identified or proposed mode of action. We also emphasise the challenges in azole potentiator development, compounded by the lack of animal testing, the overreliance on Candida albicans and Candida auris, as well as the limited understanding of compound efficacy.

Genome-wide analysis of Panonychus citri microRNAs with a focus on potential insecticidal activity of 4 microRNAs to eggs and nymphs.

Panonychus citri McGregor (Acari: Tetranychidae), a destructive citrus pest, causes considerable annual economic losses due to its short lifespan and rapid resistance development. MicroRNA (miRNA)-induced RNA interference is a promising approach for pest control because of endogenous regulation of pest growth and development. To search for miRNAs with potential insecticidal activity in P. citri, genome-wide analysis of miRNAs at different developmental stages was conducted, resulting in the identification of 136 miRNAs, including 73 known and 63 novel miRNAs. A total of 17 isomiRNAs and 12 duplicated miRNAs were characterized. MiR-1 and miR-252-5p were identified as reference miRNAs for P. citri and Tetranychus urticae. Based on differential expression analysis, treatments with miR-let-7a and miR-315 mimics and the miR-let-7a antagomir significantly reduced the egg hatch rate and resulted in abnormal egg development. Overexpression or downregulation of miR-34-5p and miR-305-5p through feeding significantly decreased the adult eclosion rate and caused molting defects. The 4 miRNAs, miR-let-7a, miR-315, miR-34-5p, and miR-305-5p, had important regulatory functions and insecticidal properties in egg hatching and adult eclosion. In general, these data advance our understanding of miRNAs in mite biology, which can assist future studies on insect-specific miRNA-based green pest control technology.

Screening of insecticidal activity of plant essential oils and extract-based formulations against four agricultural insect pests and their risk assessment

Frankliniella occidentalis (Pergande), Myzus persicae (Sulzer), Plutella xylostella (L), and Spodoptera exigua (Hübner) are notorious agricultural insect pests worldwide. Due to the rapid development of resistance to the conventional insecticides, the number of available insecticides might be reduced in a near future, and botanical insecticides can be considered as one of the potential candidates to solve this problem. In the present study, test formulations were prepared using plant essential oils and extracts as main active ingredients, and their insecticidal activity and phytotoxicity were examined. Among the combinations tested, two oil-in-water formulations of NRS-13 containing thyme white oil and NRS-24 containing basil and rosemary oils were selected based on their notable insecticidal activity and low phytotoxicity. Chemical analyses on the active essential oils, the quantitative analysis of the major components in the formulations, insecticidal activities under pot and field conditions, their acute toxicity on mammals, and ecotoxicity on fish were also examined. The NRS-13 (BaechooSaferTM) and NRS-24 (JindiOutTM) formulations showed species-specific insecticidal activity against P. xylostella and M. persicae, respectively. In addition, both formulations produced low acute oral and dermal toxicity, skin and eye irritation, and fish toxicities, which suggests those formulations based on essential oils could be considered as insecticides for pest control in small-scale environments in organic farming.

Exploiting a living biobank to delineate mechanisms underlying disease-specific chromosome instability.

Chromosome instability (CIN) is a cancer hallmark that drives tumour heterogeneity, phenotypic adaptation, drug resistance and poor prognosis. High-grade serous ovarian cancer (HGSOC), one of the most chromosomally unstable tumour types, has a 5-year survival rate of only ~30% - largely due to late diagnosis and rapid development of drug resistance, e.g., via CIN-driven ABCB1 translocations. However, CIN is also a cell cycle vulnerability that can be exploited to specifically target tumour cells, illustrated by the success of PARP inhibitors to target homologous recombination deficiency (HRD). However, a lack of appropriate models with ongoing CIN has been a barrier to fully exploiting disease-specific CIN mechanisms. This barrier is now being overcome with the development of patient-derived cell cultures and organoids. In this review, we describe our progress building a Living Biobank of over 120 patient-derived ovarian cancer models (OCMs), predominantly from HGSOC. OCMs are highly purified tumour fractions with extensive proliferative potential that can be analysed at early passage. OCMs have diverse karyotypes, display intra- and inter-patient heterogeneity and mitotic abnormality rates far higher than established cell lines. OCMs encompass a broad-spectrum of HGSOC hallmarks, including a range of p53 alterations and BRCA1/2 mutations, and display drug resistance mechanisms seen in the clinic, e.g., ABCB1 translocations and BRCA2 reversion. OCMs are amenable to functional analysis, drug-sensitivity profiling, and multi-omics, including single-cell next-generation sequencing, and thus represent a platform for delineating HGSOC-specific CIN mechanisms. In turn, our vision is that this understanding will inform the design of new therapeutic strategies.

Novel inhibitors that target bacterial virulence identified via HTS against intra-macrophage survival of Shigella flexneri.

Shigella flexneri is a facultative intracellular pathogen that causes shigellosis, a human diarrheal disease characterized by the destruction of the colonic epithelium. Novel antimicrobial compounds to treat infections are urgently needed due to the proliferation of bacterial antibiotic resistance and lack of new effective antimicrobials in the market. Our approach to find compounds that block the Shigella virulence pathway has three potential advantages: (i) resistance development should be minimized due to the lack of growth selection pressure, (ii) no resistance due to environmental antibiotic exposure should be developed since the virulence pathways are not activated outside of host infection, and (iii) the normal intestinal microbiota, which do not have the targeted virulence pathways, should be unharmed. We chose to utilize two phenotypic assays, inhibition of Shigella survival in macrophages and Shigella growth inhibition (minimum inhibitory concentration), to interrogate the 1.7 M compound screening collection subset of the GlaxoSmithKline drug discovery chemical library. A number of secondary assays on the hit compounds resulting from the primary screens were conducted, which, in combination with chemical, structural, and physical property analyses, narrowed the final hit list to 44 promising compounds for further drug discovery efforts. IMPORTANCE The rapid development of antibiotic resistance is a critical problem that has the potential of returning the world to a "pre-antibiotic" type of environment, where millions of people will die from previously treatable infections. One relatively newer approach to minimize the selection pressures for the development of resistance is to target virulence pathways. This is anticipated to eliminate any resistance selection pressure in environmental exposure to virulence-targeted antibiotics and will have the added benefit of not affecting the non-virulent microbiome. This paper describes the development and application of a simple, reproducible, and sensitive assay to interrogate an extensive chemical library in high-throughput screening format for activity against the survival of Shigella flexneri 2457T-nl in THP-1 macrophages. The ability to screen very large numbers of compounds in a reasonable time frame (~1.7 M compounds in ~8 months) distinguishes this assay as a powerful tool in further exploring new compounds with intracellular effect on S. flexneri or other pathogens with similar pathways of pathogenesis. The assay utilizes a luciferase reporter which is extremely rapid, simple, relatively inexpensive, and sensitive and possesses a broad linear range. The assay also utilized THP-1 cells that resemble primary monocytes and macrophages in morphology and differentiation properties. THP-1 cells have advantages over human primary monocytes or macrophages because they are highly plastic and their homogeneous genetic background minimizes the degree of variability in the cell phenotype (1). The intracellular and virulence-targeted selectivity of our methodology, determined via secondary screening, is an enormous advantage. Our main interest focuses on hits that are targeting virulence, and the most promising compounds with adequate physicochemical and drug metabolism and pharmacokinetic (DMPK) properties will be progressed to a suitable in vivo shigellosis model to evaluate the therapeutic potential of this approach. Additionally, compounds that act via a host-directed mechanism could be a promising source for further research given that it would allow a whole new, specific, and controlled approach to the treatment of diseases caused by some pathogenic bacteria.

Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity.

The development of durable new antiviral therapies is challenging, as viruses can evolve rapidly to establish resistance and attenuate therapeutic efficacy. New compounds that selectively target conserved viral features are attractive therapeutic candidates, particularly for combating newly emergent viral threats. The innate immune system features a sustained capability to combat pathogens through production of antimicrobial peptides (AMPs); however, these AMPs have shortcomings that can preclude clinical use. The essential functional features of AMPs have been recapitulated by peptidomimetic oligomers, yielding effective antibacterial and antifungal agents. Here, we show that a family of AMP mimetics, called peptoids, exhibit direct antiviral activity against an array of enveloped viruses, including the key human pathogens Zika, Rift Valley fever, and chikungunya viruses. These data suggest that the activities of peptoids include engagement and disruption of viral membrane constituents. To investigate how these peptoids target lipid membranes, we used liposome leakage assays to measure membrane disruption. We found that liposomes containing phosphatidylserine (PS) were markedly sensitive to peptoid treatment; in contrast, liposomes formed exclusively with phosphatidylcholine (PC) showed no sensitivity. In addition, chikungunya virus containing elevated envelope PS was more susceptible to peptoid-mediated inactivation. These results indicate that peptoids mimicking the physicochemical characteristics of AMPs act through a membrane-specific mechanism, most likely through preferential interactions with PS. We provide the first evidence for the engagement of distinct viral envelope lipid constituents, establishing an avenue for specificity that may enable the development of a new family of therapeutics capable of averting the rapid development of resistance.

Evaluation of the Stability of a 1,8-Cineole Nanoemulsion and Its Fumigant Toxicity Effect against the Pests Tetranychus urticae, Rhopalosiphum maidis and Bemisia tabaci.

Pest control is a main concern in agriculture. Indiscriminate application of synthetic pesticides has caused negative impacts leading to the rapid development of resistance in arthropod pests. Plant secondary metabolites have been proposed as a safer alternative to conventional pesticides. Monoterpenoids have reported bioactivities against important pests; however, due to their high volatility, low water solubility and chemical instability, the application of these compounds has been limited. Nanosystems represent a potential vehicle for the broad application of monoterpenoids. In this study, an 1,8-cineole nanoemulsion was prepared by the low energy method of phase inversion, characterization of droplet size distribution and polydispersity index (PDI) was carried out by dynamic light scattering and stability was evaluated by centrifugation and Turbiscan analysis. Fumigant bioactivity was evaluated against Tetranychus urticae, Rhopalosiphum maidis and Bemisia tabaci. A nanoemulsion with oil:surfactant:water ratio of 0.5:1:8.5 had a droplet size of 14.7 nm and PDI of 0.178. Formulation was stable after centrifugation and the Turbiscan analysis showed no particle migration and a delta backscattering of ±1%. Nanoemulsion exhibited around 50% more bioactivity as a fumigant on arthropods when compared to free monoterpenoid. These results suggest that nanoformulations can provide volatile compounds of protection against volatilization, improving their bioactivity.

Phage resistance formation and fitness costs of hypervirulent Klebsiella pneumoniae mediated by K2 capsule-specific phage and the corresponding mechanisms.

Phage is promising for the treatment of hypervirulent Klebsiella pneumoniae (hvKP) infections. Although phage resistance seems inevitable, we found that there still was optimization space in phage therapy for hvKP infection. The clinical isolate K. pneumoniae FK1979 was used to recover the lysis phage ΦFK1979 from hospital sewage. Phage-resistant bacteria were obtained on LB agar and used to isolate phages from sewage. The plaque assay, transmission electron microscopy (TEM), multiplicity of infection test, one-step growth curve assay, and genome analysis were performed to characterize the phages. Colony morphology, precipitation test and scanning electron microscope were used to characterize the bacteria. The absorption test, spot test and efficiency of plating (EOP) assay were used to identify the sensitivity of bacteria to phages. Whole genome sequencing (WGS) was used to identify gene mutations of phage-resistant bacteria. The gene expression levels were detected by RT-qPCR. Genes knockout and complementation of the mutant genes were performed. The change of capsules was detected by capsule quantification and TEM. The growth kinetics, serum resistance, biofilm formation, adhesion and invasion to A549 and RAW 264.7 cells, as well as G. mellonella and mice infection models, were used to evaluate the fitness and virulence of bacteria. Here, we demonstrated that K2 capsule type sequence type 86 hvKP FK1979, one of the main pandemic lineages of hvKP with thick capsule, rapidly developed resistance to a K2-specific lysis phage ΦFK1979 which was well-studied in this work to possess polysaccharide depolymerase. The phage-resistant mutants showed a marked decrease in capsule expression. WGS revealed single nucleotide polymorphism (SNP) in genes encoding RfaH, galU, sugar glycosyltransferase, and polysaccharide deacetylase family protein in the mutants. RfaH and galU were further identified as being required for capsule production and phage sensitivity. Expressions of genes involved in the biosynthesis or regulation of capsule and/or lipopolysaccharide significantly decreased in the mutants. Despite the rapid and frequent development of phage resistance being a disadvantage, the attenuation of virulence and fitness in vitro and in vivo indicated that phage-resistant mutants of hvKP were more susceptible to the immunity system. Interestingly, the newly isolated phages targeting mutants changed significantly in their plaque and virus particle morphology. Their genomes were much larger than and significantly different from that of ΦFK1979. They possessed much more functional proteins and strikingly broader host spectrums than ΦFK1979. Our study suggests that K2-specific phage has the potential to function as an antivirulence agent, or a part of phage cocktails combined with phages targeting phage-resistant bacteria, against hvKP-relevant infections.

Weed Management Studies in Wheat (Triticum aestivum L.) Through New Herbicide Molecule Aclonifen 600 SC under Climate Changing Era

Changing climate aggregates, the problem of weed management by rapid weed flora shift and resistance development. In these conditions, the best option is to use new herbicide molecules with a diverse mode of action and a wider application time window. Thus, an herbicidal trial was conducted during the Rabi 2019-20 at Agricultural Research Farm, BHU, Varanasi. The experiment was laid out in RCBD design with 8 treatments viz., control (W1), aclonifen 600SC @ 1.05 kg a.i./ha PE (W2) and early POE (W5),aclonifen 600SC @ 1.2 kg a.i./ha PE (W3) and early POE (W6), pendimethalin 30% EC @ 1.25 kg a.i./ha PE (W4), sulfosulfuron 75% WG @ 0.025 kg a.i./ha POE (W7), Farmer practice-2 hand weedings at 20 and 40 DAS (W8) and replicated thrice. Among different treatments aclonifen 600 SC @ 1.25 kg a.i./ha as pre and early post-emergence applied treatments recorded minimum weed density, weed dry matter production, highest weed control efficiency and crop persistence index. The same treatments registered better crop growth performance, and profitable yields.

Spray-Induced Gene Silencing of SsOah1 and SsCyp51 confers protection to Nicotianabenthamiana and Brassicajuncea against Sclerotiniasclerotiorum

Brassicajuncea is a major oilseed, vegetable and condiment crop in the Indian subcontinent. Its yields are compromised by the aggressive broad host range Ascomycete Sclerotiniasclerotiorum, which causes Sclerotinia Stem Rot (SSR). The limited effectiveness of fungicides, the rapid development of resistance to fungicides, and the long-term viability of sclerotia in the soil are crucial bottlenecks in controlling the disease. The discovery of the uptake of environmental RNA by fungal pathogens has opened up avenues for exploiting Spray-Induced Gene Silencing (SIGS) as a tool for mitigating plant diseases. We studied the impact of SIGS-based knockdown of S.sclerotiorumSsOah1 (SS1G_08218) and SsCyp51 (SS1G_04805), involved in virulence and fungal development, respectively, on two hosts- N.benthamiana and B.juncea. A knockdown of the two genes delayed disease initiation, reduced lesion development, and slowed disease progression within B.juncea. However, this silencing was concentration and host-dependent. Further, it also altered fungal hyphal morphology and growth, indicating its utility as a functional genomics tool. Our results identify SsCyp51 as a novel and viable target for SSR control along with SsOah1 and corroborate SIGS as a robust method for crop protection against broad-host-range fungal pathogens.

Action of Ethanolic Extract of Holerrhena pubescens on Bacterial Strains

The need to screen efficient, safe, affordable, and readily available antimicrobial agents from various medicinal plants, for their potential antimicrobial activity has become critical in light of the rapid development of microbial resistance against chemotherapeutic drugs (mainly antibiotics). Despite notable advances in the biological and phytochemical evaluation in recent years, comprehensive reviews of Holarrhena pubescens are limited. The main objective of this study is to evaluate the antimicrobial activities of this plant extract. One significant use of plant extracts can be in treating bacterial infections and develop potential antibacterial agents against multi drug resistant (MDR) and susceptible bacteria. If antimicrobial activities are present, these extracts will provide useful information for discovering new compounds with better activity and more effectiveness against resistant and susceptible bacteria responsible for infections than currently available. The ethanolic extract of leaves of Holarrhena pubescens was prepared and tested against multidrug resistant (MDR) and American type culture collection strains of bacteria. We have obtained two types of results in this experiment. The extract showed antimicrobial properties against Staphylococcus aureus (ATCC 23235), Escherichia coli (MDR) and Acinetobacter (MDR), while, it showed no antimicrobial activities along with some growth promoting role against Escherichia coli (ATCC 25922), and Klebsialla pneumoniae (MDR), which may be due to chemicals other than secondary metabolites.

Biosynthesis and characterization of cobalt nanoparticles using combination of different plants and their antimicrobial activity.

It has become crucial to biosynthesize efficient, secure, and affordable nanoparticles that we use for the treatment of various infections, including surgical site infection and wound infection, due to the rapid development of microbial resistance to numerous antibiotic drugs. The objective of the present study is to biosynthesize cobalt nanoparticles using an extract from the combined peels of garlic (Allium sativum) and onion (Allium cepa). Scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction were used to confirm the synthesis of cobalt nanoparticle (XRD). Well diffusion was used to measure antimicrobial activity. Escherichia coli, Proteus, Staphylococcus aureus, Staphylococcus cohnii, and Klebsiella pneumonia were the bacterial strains employed Both the crude prepared extract and the biosynthesized cobalt nanoparticles demonstrated efficacy against all strains of bacteria, but the crude prepared extract displayed a low zone of inhibition ranging from 10 to 13 mm, while the biosynthesized cobalt nanoparticles displayed a high zone of inhibition ranging from 20 to 24 mm.

How the plant probiotic bacteria and herbivore-induced plant volatiles (HIPVs) alter functional response of Phytoseiulus persimilis (Phytoseiidae) on the two-spotted spider mite

The two-spotted spider mite, Tetranychus urticae Koch (Acari: Tetranychidae), is one of the economically most important pests on different crops worldwide. Its management programs are normally conducted based on the usage of chemical acaricides. However, considering the side effects of acaricides and rapid resistance development, releasing the predator mite, Phytoseiulus persimilis Athias-Henriot (Acari: Phytoseiidae), is an alternative method for the control of T. urticae. In this study, the effects of plant probiotic bacteria; Bacillus pumilus INR7 (Bacillales: Bacillaceae) and Bacillus velezensis Fol (Bacillales: Bacillaceae), and herbivore-induced plant volatiles (HIPVs) (methyl jasmonate, methyl salicylate, Indole and 3-pentanol) were investigated on the functional response of P. persimilis to T. urticae eggs laid on attached leaves of kidney bean under laboratory conditions (25 ± 1 °C, 65 ± 5% RH and a photoperiod of 16:8h L:D). Densities of 2, 5, 10, 20, 30, 40, 50 and 60 prey in 10 replications were offered to the 1-day-old adult female individuals of P. persimilis during a 24-h period. The results of logistic regression analyses showed a type II functional response on all treatments. The Rogers model was used to estimate the instantaneous attack rate (a) and handling time (T<sub>h</sub>). The instantaneous attack rate had no significant difference among treatments. The handling time on B. velezensis (0.3540 ± 0.0716 h) and methyl salicylate (0.3593 ± 0.0842 h) was significantly lower than in other treatments. These results suggest that methyl salicylate and B. velezensis may have a positive effect on the foraging behavior of P. persimilis against T. urticae.

Immunometabolic control by Klebsiella pneumoniae.

Klebsiella pneumoniae is a common Gram-negative pathogen associated with community-acquired and healthcare-associated infections. Its ability to acquire genetic elements resulted in its rapid development of resistance to virtually all antimicrobial agents. Once infection is established, K. pneumoniae is able to evade the host immune response and perhaps more importantly, undergo metabolic rewiring to optimize its ability to maintain infection. K. pneumoniae lipopolysaccharide and capsular polysaccharide are central factors in the induction and evasion of immune clearance. Less well understood is the importance of immunometabolism, the intersection between cellular metabolism and immune function, in the host response to K. pneumoniae infection. Bacterial metabolism itself is perceived as a metabolic stress to the host, altering the microenvironment at the site of infection. In this review, we will discuss the metabolic responses induced by K. pneumoniae, particularly in response to stimulation with the metabolically active bacteria versus pathogen-associated molecular patterns alone, and their implications in shaping the nature of the immune response and the infection outcome. A better understanding of the immunometabolic response to K. pneumoniae may help identify new targets for therapeutic intervention in the treatment of multidrug-resistant bacterial infections.

Rapid development of cefiderocol resistance in a carbapenem-resistant Pseudomonas aeruginosa isolate associated with mutations in the pyoverdine biosynthesis pathway

Here we report the in vivo development of cefiderocol resistance within 11 days after therapy initiation in a critically ill patient with bloodstream infection, infection of peri-anal fistula, and pneumonia caused by a VIM-2 harbouring, carbapenem-resistant Pseudomonas aeruginosa. Compared to a cefiderocol-naïve P. aeruginosa blood culture isolate, agar diffusion susceptibility testing found a reduced cefiderocol inhibition zone diameter in a P. aeruginosa recovered from peri-anal abscess tissue cultures after initiation of cefiderocol therapy. Subsequent whole-genome sequencing suggested that both isolates were of clonal origin. Comparison of genomes found an accumulation of missense mutations within pvdP, pvdE, pvdJ, and pvdD (i.e. genes associated with biosynthesis of pyoverdine), the main siderophore produced by P. aeruginosa. Quantification of pyoverdine production under iron-depleted conditions showed a significantly (P=0.0003) higher pyoverdine production by the cefiderocol-resistant isolate. While pyoverdine quantity alone appears not to be decisive for cefiderocol resistance, the reported case highlights the potentially rapid emergence of cefiderocol resistance in P. aeruginosa and points towards a potential involvement of iron up-take systems in this process.

Campylobacteriosis in Poultry: A Review

Campylobacter is common in poultry, including layer and broiler chickens, geese, ducks, and turkeys. This review aimed to emphasize the prevalence of campylobacteriosis, recent poultry diagnoses, and strict prevention measures. Campylobacter species colonize the intestines of poultry and waterfowl but are generally nonpathogenic in poultry. However, they are the most common bacterial cause of sporadic human enteritis in both developed and developing countries. The main species responsible for campylobacteriosis is Campylobacter jejuni, followed by Campylobacter coli. A number of other Campylobacter species, such as Campylobacter lari, fetus, upsaliensis, and hyointestinalis are rarely associated with campylobacteriosis. Campylobacter hepaticus is the species linked to spotty liver disease in layers and breeder chickens, and it may be the etiological agent of the disease previously known as avian vibrionic hepatitis. The most prevalent infection source for Campylobacter is environmental contamination from poultry droppings. However, some Campylobacter species can be transmitted vertically, either on the surface of eggs or via trans-ovarian transmission in addition to consumption of contaminated feed or water. Due to the non-specific clinical signs such as diarrhea and weight loss, diagnosing campylobacteriosis in poultry requires culture or polymerase chain reaction tests. Little is known about the available vaccine or effective antibiotic treatment due to the rapid development of antibiotic resistance. Therefore, strict biosecurity measures play a crucial role in preventing Campylobacter infection in commercial poultry. These measures include decontaminating housing between flocks, preventing the entry of rodents, wild birds, and animals, and eradicating insects. To control campylobacteriosis and reduce infection risks, it is important to implement efficient on-farm biosecurity measures, conduct regular inspections of workers at meat processing plants and poultry farms, and ensure thorough preparation of chicken meat and eggs before consumption. These measures are vital in minimizing the Campylobacter transmission from both broiler and laying chickens, thereby reducing the risk of foodborne diseases caused by contaminated food.