-
Antimicrobial Agents and Chemotherapy Jun 2024Intrinsic resistance to macrolides in Gram-negative bacteria is primarily attributed to the low permeability of the outer membrane, though the underlying genetic and...
Intrinsic resistance to macrolides in Gram-negative bacteria is primarily attributed to the low permeability of the outer membrane, though the underlying genetic and molecular mechanisms remain to be fully elucidated. Here, we used transposon directed insertion-site sequencing (TraDIS) to identify chromosomal non-essential genes involved in intrinsic resistance to a macrolide antibiotic, tilmicosin. We constructed two highly saturated transposon mutant libraries of >290,000 and >390,000 unique Tn5 insertions in a clinical enterotoxigenic strain (ETEC5621) and in a laboratory strain (K-12 MG1655), respectively. TraDIS analysis identified genes required for growth of ETEC5621 and MG1655 under 1/8 MIC ( = 15 and 16, respectively) and 1/4 MIC ( = 38 and 32, respectively) of tilmicosin. For both strains, 23 genes related to lipopolysaccharide biosynthesis, outer membrane assembly, the Tol-Pal system, efflux pump, and peptidoglycan metabolism were enriched in the presence of the antibiotic. Individual deletion of genes ( = 10) in the wild-type strains led to a 64- to 2-fold reduction in MICs of tilmicosin, erythromycin, and azithromycin, validating the results of the TraDIS analysis. Notably, deletion of or , which impairs the outer membrane, led to the most significant decreases in MICs of all three macrolides in ETEC5621. Our findings contribute to a genome-wide understanding of intrinsic macrolide resistance in , shedding new light on the potential role of the peptidoglycan layer. They also provide an proof of concept that can be sensitized to macrolides by targeting proteins maintaining the outer membrane such as SurA and WaaG.
PubMed: 38940570
DOI: 10.1128/aac.00452-24 -
Frontiers in Bioscience (Landmark... Jun 2024The inhibitors of mammalian target of rapapmycin (mTOR), everolimus, temsirolimus and rapamycin, have a wide range of clinical utility; however, as is inevitably the... (Review)
Review
The inhibitors of mammalian target of rapapmycin (mTOR), everolimus, temsirolimus and rapamycin, have a wide range of clinical utility; however, as is inevitably the case with other chemotherapeutic agents, resistance development constrains their effectiveness. One putative mechanism of resistance is the promotion of autophagy, which is a direct consequence of the inhibition of the mTOR signaling pathway. Autophagy is primarily considered to be a cytoprotective survival mechanism, whereby cytoplasmic components are recycled to generate energy and metabolic intermediates. The autophagy induced by everolimus and temsirolimus appears to play a largely protective function, whereas a cytotoxic function appears to predominate in the case of rapamycin. In this review we provide an overview of the autophagy induced in response to mTOR inhibitors in different tumor models in an effort to determine whether autophagy targeting could be of clinical utility as adjuvant therapy in association with mTOR inhibition.
Topics: Humans; Autophagy; TOR Serine-Threonine Kinases; MTOR Inhibitors; Animals; Neoplasms; Signal Transduction; Antineoplastic Agents; Cytoprotection; Sirolimus
PubMed: 38940039
DOI: 10.31083/j.fbl2906231 -
Open Forum Infectious Diseases Jun 2024Antimicrobial resistance (AMR) is a global threat to infectious disease control, particularly among recently hospitalized children. We sought to determine the prevalence...
BACKGROUND
Antimicrobial resistance (AMR) is a global threat to infectious disease control, particularly among recently hospitalized children. We sought to determine the prevalence and mitigating factors of resistance in enteric among children discharged from health facilities in western Kenya.
METHODS
Between June 2016 and November 2019, children aged 1 to 59 months were enrolled at the point of discharge from the hospital. was isolated by microbiological culture from rectal swabs at baseline. β-Lactamases and macrolide resistance-conferring genes were detected by polymerase chain reaction. A modified Poisson regression model was used to assess the predictors (A) and CTX-M-type extended-spectrum β-lactamase (ESBL).
RESULTS
Of the 238 children whose isolates were tested, 91 (38.2%) and 109 (45.8%) had detectable CTX-M-type ESBL and (A) genes, respectively. Antibiotic treatment during hospitalization (adjusted prevalence ratio [aPR], 2.47; 95% CI, 1.12-5.43; = .025), length of hospitalization (aPR, 1.42; 95% CI, 1.00-2.01; = .052), and the practice of open defecation (aPR, 2.47; 95% CI, 1.40-4.36; = .002) were independent predictors for CTX-M-type ESBL and (A) genes. Pneumococcal vaccination was associated with a 43% lower likelihood of CTX-M-type ESBL (aPR, 0.57; 95% CI, .38-.85; = .005), while measles vaccination was associated with a 32% lower likelihood of (A) genes (aPR, 0.68; 95% CI, .49-.93; = .017) in isolates.
CONCLUSIONS
Among children discharged from the hospital, history of vaccination, shorter hospital stay, lack of in-hospital antibiotic exposure, and improved sanitation were associated with a lower likelihood of AMR genes. To mitigate the continued spread of AMR, AMR control programs should consider strategies beyond antimicrobial stewardship, including improvements in sanitation, increased vaccine coverage, and the development of novel vaccines.
PubMed: 38938894
DOI: 10.1093/ofid/ofae307 -
Open Veterinary Journal May 2024Young farm animals are susceptible to opportunistic infections which may cause economic losses due to mortality and poor weight gain. The development of antimicrobial...
BACKGROUND
Young farm animals are susceptible to opportunistic infections which may cause economic losses due to mortality and poor weight gain. The development of antimicrobial resistance and the desire to improve therapy efficacy and safety are the reasons to seek for new antibacterial drugs ensuring rapid recovery with minimum adverse events.
AIM
To estimate the efficacy of DOKSI AVZ 500 in respiratory pathologies in young pigs.
METHODS
The study was conducted in 65-70-day-old Yorkshire piglets with signs of bacterial respiratory pathologies. The animals were treated with the test drug for 3 or 5 days. The reference group received TETRAMAX 500 which is similar to the test drug in terms of chemical structure, mechanism of action, and activity spectrum. The animal's status was assessed using clinical examination, clinical blood count, and bacteriological tests.
RESULTS
Both test and reference drugs were well tolerated and ensured the animal recovery within about 4 days. The recovery was accompanied by normalization of hematological parameters and flora composition. The bacterium associated with the disease development, , was virtually completely eliminated in all groups. No adverse events were noted. After the treatment, all the animals readily gained weight and live market quality.
CONCLUSION
DOKSI AVZ 500 was a highly efficient therapy for respiratory pathologies caused by the resident opportunistic flora in piglets. It has also shown noninferiority TETRAMAX 500 in terms of all the health-related parameters and thus can be recommended for introduction in veterinary practice in pig farms.
Topics: Animals; Swine; Swine Diseases; Anti-Bacterial Agents; Respiratory Tract Infections; Female; Male; Tylosin
PubMed: 38938427
DOI: 10.5455/OVJ.2024.v14.i5.2 -
BMC Infectious Diseases Jun 2024Refractory Helicobacter pylori (H. pylori) infection inevitably increase the difficulty of drug selection. Here, we described our experience with the use of a novel... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Refractory Helicobacter pylori (H. pylori) infection inevitably increase the difficulty of drug selection. Here, we described our experience with the use of a novel tetravalent IgY against H. pylori for the treatment of patients with refractory H. pylori infection.
METHODS
Patients were randomly assigned to receive the standard quadruple therapy (amoxicillin, clarithromycin, omeprazole and bismuth potassium citrate ) for 2 weeks or 250 mg of avian polyclonal IgY orally twice a day for 4 weeks. The binding efficacy of IgY to H. pylori antigens was detected by western blotting. C-urea breath test was performed to evaluate the eradication therap's efficacy. The side effects of IgY were evaluated via various routine tests. The questionnaire was used to gather clinical symptoms and adverse reactions.
RESULTS
Western blot analysis showed that tetravalent IgY simultaneously bind to VacA, HpaA, CagA and UreB of H. pylori. Tetravalent IgY had an eradication rate of 50.74% in patients with refractory H. pylori and an inhibition rate of 50.04% against DOB (delta over baseline) of C-urea. The symptom relief rate was 61.76% in thirty-four patients with clinical symptoms, and no adverse reactions were observed during tetravalent IgY treatment period.
CONCLUSIONS
Polyclonal avian tetravalent IgY reduced H. pylori infection, and showed good efficacy and safety in the treatment of refractory H. pylori infection patients, which represented an effective therapeutic option of choice for patients with refractory H. pylori infection.
Topics: Humans; Helicobacter Infections; Male; Female; Helicobacter pylori; Middle Aged; Immunoglobulins; Adult; Anti-Bacterial Agents; Treatment Outcome; Aged; Drug Therapy, Combination; Clarithromycin; Amoxicillin; Young Adult; Antibodies, Bacterial
PubMed: 38937679
DOI: 10.1186/s12879-024-09498-4 -
Scientific Reports Jun 2024Nasally colonized staphylococci carry antibiotic resistance genes and may lead to serious opportunistic infections. We are investigating nasal carriage of Staphylococcus...
Nasally colonized staphylococci carry antibiotic resistance genes and may lead to serious opportunistic infections. We are investigating nasal carriage of Staphylococcus aureus and Staphylococci other than S. aureus (SOSA) among young volunteers in Egypt to determine their risk potential. Nasal swabs collected over 1 week in June 2019 from 196 volunteers were cultured for staphylococcus isolation. The participants were interviewed to assess sex, age, general health, hospitalization and personal hygiene habits. Identification was carried out using biochemical tests and VITEK 2 automated system. Disc diffusion and minimum inhibitory concentration tests were performed to determine antibiotic susceptibility. Screening for macrolide resistance genes (ermA, ermB, ermC, ermT and msrA) was performed using polymerase chain reaction. Thirty four S. aureus and 69 SOSA were obtained. Multi-drug resistance (MDR) was detected among most staphylococcal species, ranging from 30.77% among S. hominis to 50% among S. epidermidis. Phenotypic resistance to all tested antibiotics, except for linezolid, was observed. Susceptibility to rifampicin, vancomycin and teicoplanin was highest. ermB showed the highest prevalence among all species (79.41% and 94.2% among S. aureus and SOSA, respectively), and constitutive macrolide-lincosamide-streptogramin B (MLS) resistance was equally observed in S. aureus and SOSA (11.11% and 16.22%, respectively), whereas inducible MLS resistance was more often found in S. aureus (77.78% and 43.24%, respectively). The species or resistance level of the carried isolates were not significantly associated with previous hospitalization or underlying diseases. Although over all colonization and carriage of resistance genes are within normal ranges, the increased carriage of MDR S. aureus is alarming. Also, the fact that many macrolide resitance genes were detected should be a warning sign, particularly in case of MLS inducible phenotype. More in depth analysis using whole genome sequencing would give a better insight into the MDR staphylococci in the community in Egypt.
Topics: Humans; Egypt; Female; Male; Staphylococcus; Microbial Sensitivity Tests; Staphylococcal Infections; Anti-Bacterial Agents; Adult; Phenotype; Young Adult; Genotype; Staphylococcus aureus; Drug Resistance, Multiple, Bacterial; Adolescent
PubMed: 38937465
DOI: 10.1038/s41598-024-60924-8 -
PLoS Neglected Tropical Diseases Jun 2024Lymphatic filariasis (LF) remains a significant global issue. To eliminate LF as a public health problem, the World Health Organization (WHO) recommends multiple rounds...
BACKGROUND
Lymphatic filariasis (LF) remains a significant global issue. To eliminate LF as a public health problem, the World Health Organization (WHO) recommends multiple rounds of mass drug administration (MDA). In certain scenarios, including when elimination targets have not been met with two-drug MDA, triple-drug MDA (using ivermectin, diethylcarbamazine and albendazole) is recommended. In this study, we report on antigen (Ag) and microfilaria (Mf) prevalence in eight primary sampling units (PSUs) in Samoa 4.5 years after one round of triple-drug MDA.
METHODOLOGY
In 2023, community surveys were conducted in eight PSUs that had been surveyed previously in 2018 (between 1.5 and 3.5 months post triple-drug MDA) and 2019 (six to eight-months post triple-drug MDA). Fifteen houses were randomly selected in each PSU with household members aged ≥ 5 years invited to participate. Blood samples were tested for Ag and Mf.
PRINCIPAL FINDINGS
Ag-positive participants were observed in six of the eight PSUs, and Ag prevalence was significantly above the 1% threshold in four PSUs. The presence of Mf-positive participants in five PSUs confirms the presence of residual active infections.
CONCLUSIONS/SIGNIFICANCE
This study provides evidence of persistent LF transmission in Samoa 4.5 years after one round of triple-drug MDA, confirming that one round was insufficient for interruption of transmission in this setting. Our findings highlight the negative impact of delaying MDA rounds, for example, due to public health emergencies.
Topics: Elephantiasis, Filarial; Humans; Mass Drug Administration; Albendazole; Samoa; Diethylcarbamazine; Ivermectin; Male; Female; Adult; Filaricides; Middle Aged; Adolescent; Animals; Young Adult; Child; Prevalence; Antigens, Helminth; Drug Therapy, Combination; Child, Preschool; Wuchereria bancrofti; Aged
PubMed: 38935622
DOI: 10.1371/journal.pntd.0012236 -
Zeitschrift Fur Naturforschung. C,... Jun 2024Chemical investigation of the fungal endophyte sp. isolated from leaves of , collected in Cameroon, resulted in the previously undescribed 10-membered macrolide, and...
Chemical investigation of the fungal endophyte sp. isolated from leaves of , collected in Cameroon, resulted in the previously undescribed 10-membered macrolide, and two known natural products. The structures of the xylatolides A and B were unambiguously identified by their mass spectra and by extensive 1D and 2D NMR spectroscopic analysis, featuring a 10-membered lactone core structure with oxygenated substituents and an unsubstituted 10-alkyl chain presenting seven carbon atoms. Compounds were screened for their cytotoxic potential against the human HepG2 hepatocellular carcinoma cells and HCT-116 cells (human colon carcinoma cell line). Moreover, the isolated compounds were also assayed against a small panel of sensitive strains including the bacterial species , , and as well as against the fungal species . However, no significant activities were found.
PubMed: 38934215
DOI: 10.1515/znc-2023-0091 -
The Pan African Medical Journal 2024Lymphatic filariasis is a neglected tropical disease that affects the lymphatic system of humans. The major etiologic agent is a nematode called Wuchereria bancrofti,... (Review)
Review Meta-Analysis
Lymphatic filariasis is a neglected tropical disease that affects the lymphatic system of humans. The major etiologic agent is a nematode called Wuchereria bancrofti, but Brugia malayi and Brugia timoriare sometimes encountered as causative agents. Mosquitoes are the vectors while humans the definitive hosts respectively. The burden of the disease is heavier in Nigeria than in other endemic countries in Africa. This occurs with increasing morbidity and mortality at different locations within the country, the World Health Organization recommended treatments for lymphatic filariasis include the use of Albendazole (400mg) twice per year in co-endemic areas with loa loa, Ivermectin (200mcg/kg) in combination with Albendazole (400mg) in areas that are co-endemic with onchocerciasis, ivermectin (200mcg/kg) with diethylcarbamazine citrate (DEC) (6mg/kg) and albendazole (400mg) in areas without onchocerciasis. This paper covered a systematic review, meta-analysis, and scoping review on lymphatic filariasis in the respective geopolitical zones within the country. The literature used was obtained through online search engines including PubMed and Google Scholar with the heading "lymphatic filariasis in the name of the state", Nigeria. This review revealed an overall prevalence of 11.18% with regional spread of Northwest (1.59%), North Central and North East, (4.52%), South West (1.26%), and South-South with South East (3.81%) prevalence. The disease has been successfully eliminated in Argungu local government areas (LGAs) of Kebbi State, Plateau, and Nasarawa States respectively. Most clinical manifestations (31.12%) include hydrocele, lymphedema, elephantiasis, hernia, and dermatitis. Night blood samples are appropriate for microfilaria investigation. Sustained MDAs, the right testing methods, early treatment of infected cases, and vector control are useful for the elimination of lymphatic filariasis for morbidity management and disability prevention in the country. Regional control strategies, improved quality monitoring of surveys and intervention programs with proper records of morbidity and disability requiring intervention are important approaches for the timely elimination of the disease in Nigeria.
Topics: Elephantiasis, Filarial; Humans; Nigeria; Animals; Wuchereria bancrofti; Filaricides; Albendazole; Neglected Diseases; Ivermectin; Brugia malayi
PubMed: 38933431
DOI: 10.11604/pamj.2024.47.142.39746 -
Pharmaceuticals (Basel, Switzerland) May 2024There are more than 170 known species of non-tuberculous mycobacteria, and some are responsible for serious diseases in people infected with them. One of these is Buruli...
There are more than 170 known species of non-tuberculous mycobacteria, and some are responsible for serious diseases in people infected with them. One of these is Buruli ulcers, a neglected tropical disease endemic in more than 33 countries and caused by , which infects skin tissue. Treatment consists of a long-term regimen combining the use of oral rifampin with another anti-tuberculosis drug (e.g., clarithromycin). Patients in these countries face difficulties in accessing and adhering to this therapy. This study investigates the feasibility of formulating stable, optimized clarithromycin as a topical cutaneous cream. The cream was formulated, and its stability was evaluated under different storage temperature conditions and using a stability indicator method. The results showed that the clarithromycin cream was stable for at least 60 days, even at extreme temperatures (40 °C). In conclusion, the data presented here demonstrate the stability of a new form of topical cutaneous clarithromycin, which may offer a new approach to the treatment of Buruli ulcers and clarithromycin-sensitive infections.
PubMed: 38931358
DOI: 10.3390/ph17060691