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Nature Communications Jul 2023The ever-growing rise of antibiotic resistance among bacterial pathogens is one of the top healthcare threats today. Although combination antibiotic therapies represent...
The ever-growing rise of antibiotic resistance among bacterial pathogens is one of the top healthcare threats today. Although combination antibiotic therapies represent a potential approach to more efficiently combat infections caused by susceptible and drug-resistant bacteria, only a few known drug pairs exhibit synergy/cooperativity in killing bacteria. Here, we discover that well-known ribosomal antibiotics, hygromycin A (HygA) and macrolides, which target peptidyl transferase center and peptide exit tunnel, respectively, can act cooperatively against susceptible and drug-resistant bacteria. Remarkably, HygA slows down macrolide dissociation from the ribosome by 60-fold and enhances the otherwise weak antimicrobial activity of the newest-generation macrolide drugs known as ketolides against macrolide-resistant bacteria. By determining a set of high-resolution X-ray crystal structures of drug-sensitive wild-type and macrolide-resistant Erm-methylated 70S ribosomes in complex with three HygA-macrolide pairs, we provide a structural rationale for the binding cooperativity of these drugs and also uncover the molecular mechanism of overcoming Erm-type resistance by macrolides acting together with hygromycin A. Altogether our structural, biochemical, and microbiological findings lay the foundation for the subsequent development of synergistic antibiotic tandems with improved bactericidal properties against drug-resistant pathogens, including those expressing erm genes.
Topics: Macrolides; Anti-Bacterial Agents; Cinnamates; Hygromycin B; Ketolides; Protein Synthesis Inhibitors; Bacteria; Drug Resistance, Bacterial
PubMed: 37452045
DOI: 10.1038/s41467-023-39653-5 -
Clinical Infectious Diseases : An... Nov 2023Mycoplasma genitalium (MG) is on the CDC Watch List of Antimicrobial Resistance Threats, yet there is no systematic surveillance to monitor change.
BACKGROUND
Mycoplasma genitalium (MG) is on the CDC Watch List of Antimicrobial Resistance Threats, yet there is no systematic surveillance to monitor change.
METHODS
We initiated surveillance in sexual health clinics in 6 cities, selecting a quota sample of urogenital specimens tested for gonorrhea and/or chlamydia. We abstracted patient data from medical records and detected MG and macrolide-resistance mutations (MRMs) by nucleic acid amplification testing. We used Poisson regression to estimate adjusted prevalence ratios (aPRs) and 95% CIs, adjusting for sampling criteria (site, birth sex, symptom status).
RESULTS
From October-December 2020 we tested 1743 urogenital specimens: 57.0% from males, 46.1% from non-Hispanic Black persons, and 43.8% from symptomatic patients. MG prevalence was 16.6% (95% CI: 14.9-18.5%; site-specific range: 9.9-23.5%) and higher in St Louis (aPR: 1.9; 1.27-2.85), Greensboro (aPR: 1.8; 1.18-2.79), and Denver (aPR: 1.7; 1.12-2.44) than Seattle. Prevalence was highest in persons <18 years (30.4%) and declined 3% per each additional year of age (aPR: .97; .955-.982). MG was detected in 26.8%, 21.1%, 11.8%, and 15.4% of urethritis, vaginitis, cervicitis, and pelvic inflammatory disease (PID), respectively. It was present in 9% of asymptomatic males and 15.4% of asymptomatic females, and associated with male urethritis (aPR: 1.7; 1.22-2.50) and chlamydia (aPR: 1.7; 1.13-2.53). MRM prevalence was 59.1% (95% CI: 53.1-64.8%; site-specific range: 51.3-70.6%). MRMs were associated with vaginitis (aPR: 1.8; 1.14-2.85), cervicitis (aPR: 3.5; 1.69-7.30), and PID cervicitis (aPR: 1.8; 1.09-3.08).
CONCLUSIONS
MG infection is common in persons at high risk of sexually transmitted infections; testing symptomatic patients would facilitate appropriate therapy. Macrolide resistance is high and azithromycin should not be used without resistance testing.
Topics: Female; Humans; Male; Anti-Bacterial Agents; Urethritis; Mycoplasma genitalium; Uterine Cervicitis; Sexual Health; Macrolides; Drug Resistance, Bacterial; Pelvic Inflammatory Disease; Vaginitis; Mycoplasma Infections; Prevalence
PubMed: 37402645
DOI: 10.1093/cid/ciad405 -
Poultry Science Mar 2023Riemerella anatipestifer is an important pathogen in waterfowl, and is generally multidrug resistant. This study assessed the current status of Riemerella anatipestifer...
Riemerella anatipestifer is an important pathogen in waterfowl, and is generally multidrug resistant. This study assessed the current status of Riemerella anatipestifer antibiotic resistance and antibiotic-resistance genes (ARGs), compared the results of different detection methods, and evaluated a new method of studying the association between antibiotic resistance and ARGs in Riemerella anatipestifer. In this study, 51 strains of Riemerella anatipestifer were isolated from ducks on several farms, their resistance to 28 antibiotics was assessed, and the isolates were subjected to whole-genome sequencing. The number of ARGs carried by Riemerella anatipestifer was predicted, compared, and analyzed, and the consistency between ARGs and antibiotic-resistance phenotypes was assessed. The potential for loss of resistance genes during the sequencing and assembly of genome-wide framework map was assessed, and a new ARG detection method was pilot tested. The 51 strains of Riemerella anatipestifer were multidrug resistant (MDR) and had high level of resistance to aminoglycosides, trimethoprim, lincosamides, polypeptides, and macrolides. Based on the genome-wide framework map of the 51 strains, 3 local databases of ABRicate software and 1 online database of CARD website were used to detect ARGs, and a mean of 4 to 5 ARGs were identified per isolate. Although the detection results differed according to the database used, the general performance was consistent. The online website detected more types of ARGs than the ABRicate software. The association between ARGs and antibiotic-resistance phenotypes was assessed, and the ermF gene was identified as a possible key ARGs regulating macrolide resistance of Riemerella anatipestifer. The method used to investigate and detect Riemerella anatipestifer ARGs was convenient and rapid, and had strong accuracy and pertinence. The ARGs detection method reported here combined the advantages of PCR and genome detection, and could greatly reduce workload and detect ARGs more precisely.
Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Bacterial; Macrolides; Chickens; Riemerella; Ducks; Flavobacteriaceae Infections; Poultry Diseases
PubMed: 36580762
DOI: 10.1016/j.psj.2022.102405 -
Reproductive Toxicology (Elmsford, N.Y.) Mar 2021This study investigated the risk of congenital heart defects (CHD) and other congenital anomalies (CA) associated with first trimester use of macrolide antibiotics...
This study investigated the risk of congenital heart defects (CHD) and other congenital anomalies (CA) associated with first trimester use of macrolide antibiotics (mainly erythromycin, spiramycin, clarithromycin and azithromycin) and lincosamides (clindamycin) using a case-malformed control design. Data included 145,936 babies with a CA diagnosis (livebirths, stillbirths and terminations of pregnancy for CA) from 15 population-based EUROCAT registries in 13 European countries, covering 9 million births 1995-2012. Cases were babies with CHD, anencephaly, orofacial clefts, genital and limb reduction anomalies associated with antibiotic exposure in the literature. Controls were babies with other CA or genetic conditions. Main outcomes were odds ratios adjusted (AOR) for maternal age and registry, with 95 % Confidence Intervals (95 %CI). Macrolide and lincosamide exposure was recorded for 307 and 28 cases, 72 and 4 non-genetic controls, 57 and 7 genetic controls, respectively. AOR for CHD was not significantly raised (AOR 0.94, 95 %CI: 0.70-1.26 vs non-genetic controls; AOR 1.01, 95 %CI: 0.73-1.41 vs genetic controls), nor significantly raised for any specific macrolide. The risk of atrioventricular septal defect was significantly raised with exposure to any macrolide (AOR 2.98; 95 %CI: 1.48-6.01), erythromycin (AOR 3.68, 95 %CI: 1.28-10.61), and azithromycin (AOR 4.50, 95 %CI: 1.30-15.58). Erythromycin, clarithromycin, azithromycin, and clindamycin were associated with an increased risk of at least one other CA. Further research is needed on the risk of specific CA associated with macrolide and lincosamide use in the first trimester, particularly relevant for the potential use of azithromycin in the treatment of COVID-19.
Topics: Abnormalities, Drug-Induced; Anti-Bacterial Agents; Case-Control Studies; Female; Heart Defects, Congenital; Humans; Lincosamides; Macrolides; Pregnancy; Pregnancy Trimester, First; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33454317
DOI: 10.1016/j.reprotox.2021.01.006 -
Respiratory Medicine Oct 2023Macrolide-resistant Mycobacterium avium complex (MAC) disease is very difficult to cure. Macrolide-resistance emerges in patients and is largely preventable by...
BACKGROUND
Macrolide-resistant Mycobacterium avium complex (MAC) disease is very difficult to cure. Macrolide-resistance emerges in patients and is largely preventable by appropriate screening and treatment practices.
METHODS
Patients with macrolide-resistant MAC isolates between March 2019 and March 2022 were retrieved from the mycobacteriology reference laboratory database at Radboudumc, Nijmegen, the Netherlands. Clinical consultation reports were extracted from the database to assess the cause of macrolide resistance.
RESULTS
Sixteen patients with macrolide-resistant MAC disease were included, from a total of 815 patients with MAC isolates (2%); Macrolide monotherapy in bronchiectasis or CF was the most frequent cause of development of macrolide-resistance MAC disease (n = 8; 50%). Short (n = 3; mean duration 9 months, range 6-12) or guideline non-compliant (n = 2) treatment regimens and patient non-adherence (n = 2) were other key causes of macrolide-resistance.
CONCLUSIONS
Macrolide monotherapy after inappropriate screening is the most frequent cause of macrolide-resistant Mycobacterium avium complex disease in the Netherlands. Educational efforts are needed to prevent this.
Topics: Humans; Mycobacterium avium Complex; Anti-Bacterial Agents; Macrolides; Mycobacterium avium-intracellulare Infection; Drug Resistance, Bacterial; Lung Diseases
PubMed: 37481170
DOI: 10.1016/j.rmed.2023.107366 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2020The nargenicin family of antibiotic macrolides comprise a group of bacterial natural products with a rare ether bridged cis-decalin moiety and a narrow spectrum of... (Review)
Review
The nargenicin family of antibiotic macrolides comprise a group of bacterial natural products with a rare ether bridged cis-decalin moiety and a narrow spectrum of activity. Most family members were identified almost four decades ago and were placed on the shelf due to the numbers of broad-spectrum compounds available at the time. However, in light of rising rates of antimicrobial resistance, there has been a renewed interest in the use of narrow-spectrum antimicrobials. Here, we review the history of this family of compounds, including synthetic approaches, and highlight the recently uncovered genetic basis for nargenicin production. Given the renewed pharmaceutical interest in these compounds, we also investigate structure-activity relationships among these molecules, with a view to the future development of members of this unusual antibiotic family.
Topics: Anti-Bacterial Agents; Bridged-Ring Compounds; Humans; Lactones; Macrolides; Naphthalenes; Structure-Activity Relationship
PubMed: 31667915
DOI: 10.1002/chem.201904053 -
Microbiology Spectrum Dec 2023This study first reported the effector kinetics of the new non-fluorinated quinolone, nemonoxacin, against macrolide-resistant (MRMP) and macrolide susceptible (MSMP)...
This study first reported the effector kinetics of the new non-fluorinated quinolone, nemonoxacin, against macrolide-resistant (MRMP) and macrolide susceptible (MSMP) strains along with other antimicrobial agents. The time-kill assays and pharmacodynamic analysis showed that nemonoxacin has significant mycoplasmacidal activity against MRMP and MSMP. This study paves the road to establish appropriate dosing protocols of a new antimicrobial drug for children infected with .
Topics: Child; Humans; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Anti-Bacterial Agents; Quinolones; Macrolides; Drug Resistance, Bacterial; Microbial Sensitivity Tests
PubMed: 37975686
DOI: 10.1128/spectrum.02431-23 -
Organic & Biomolecular Chemistry Mar 2023Antimycins are one of the well-known antifungal metabolites produced by bacteria. Neoantimycin and its analogues, the ring-expanded antimycins featuring a 15-membered...
Antimycins are one of the well-known antifungal metabolites produced by bacteria. Neoantimycin and its analogues, the ring-expanded antimycins featuring a 15-membered tetraester ring, have been shown to be effective regulators of the oncogenic proteins GRP78/BiP and K-Ras. Isoneoantimycin was isolated from IFO12773 (ISP 5063) as a minor metabolite during the fermentation of neoantimycin and is the first reported antibiotic of the antimycin family without the macrolide core. In this study, we explored the total synthesis and stereochemical assignment of isoneoantimycin as an approach to perform structure-activity studies on neoantimycins. Taking the neoantimycin biosynthesis pathway into account, we presumed that the stereochemistry of isoneoantimycin is the same as that of neoantimycin. The synthesis of our target molecule with the (1,2,5,6,14,15,17) configuration has been achieved by using chiral-pool building blocks. A comparison of the spectroscopic data between the synthetic and natural samples verified our presumption of the stereochemistry of natural isoneoantimycin.
Topics: Antimycin A; Anti-Bacterial Agents; Organic Chemicals
PubMed: 36857695
DOI: 10.1039/d3ob00099k -
BMC Microbiology Aug 2023The microbiome of the human gut serves a role in a number of physiological processes, but can be altered through effects of age, diet, and disturbances such as...
BACKGROUND
The microbiome of the human gut serves a role in a number of physiological processes, but can be altered through effects of age, diet, and disturbances such as antibiotics. Several studies have demonstrated that commonly used antibiotics can have sustained impacts on the diversity and the composition of the gut microbiome. The impact of the two most overused antibiotics, azithromycin, and amoxicillin, in the human microbiome has not been thoroughly described. In this study, we recruited a group of individuals and unrelated controls to decipher the effects of the commonly used antibiotics amoxicillin and azithromycin on their gut microbiomes.
RESULTS
We characterized the gut microbiomes by metagenomic sequencing followed by characterization of the resulting microbial communities. We found that there were clear and sustained effects of the antibiotics on the gut microbial community with significant alterations in the representations of Bifidobacterium species in response to azithromycin (macrolide antibiotic). These results were supported by significant increases identified in putative antibiotic resistance genes associated with macrolide resistance. Importantly, we did not identify these trends in the unrelated control individuals. There were no significant changes observed in other members of the microbial community.
CONCLUSIONS
As we continue to focus on the role that the gut microbiome plays and how disturbances induced by antibiotics might affect our overall health, elucidating members of the community most affected by their use is of critical importance to understanding the impacts of common antibiotics on those who take them. Clinical Trial Registration Number NCT05169255. This trial was retrospectively registered on 23-12-2021.
Topics: Humans; Anti-Bacterial Agents; Amoxicillin; Azithromycin; Metagenomics; Macrolides; Drug Resistance, Bacterial
PubMed: 37528343
DOI: 10.1186/s12866-023-02949-z -
Journal of Medical Microbiology Jun 2022Nontuberculous mycobacteria (NTM) infections are increasing worldwide and are relatively resistant to many of the first- and second-line drugs to treat tuberculosis....
Nontuberculous mycobacteria (NTM) infections are increasing worldwide and are relatively resistant to many of the first- and second-line drugs to treat tuberculosis. Macrolide antibiotics, such as clarithromycin and azithromycin, are the key drugs for treating NTM infections. Fidaxomicin is a macrolide antibiotic that is widely used in treating infections, and has high activity against especially multidrug-resistant tuberculosis (MDR-TB) and has no cross-resistance with rifampicin. Fidaxomicin may have activity against NTM strains. To find that whether the macrolide antibiotic fidaxomicin has activity against NTM strains. Fidaxomicin used in this study was firstly tested on reference strains and has shown to be effective and workable. And then 28 rapidly growing mycobacteria (RGM), 12 slowly growing mycobacteria (SGM) reference strains and 103 NTM clinical isolates were tested by the microplate-based AlamarBlue assay (MABA) method to determine the MICs. Fidaxomicin, rifampicin and clarithromycin were tested against omplex subspecies 14 . and 5 . strains for inducible resistance determination. In total, 21 out of 28 RGM and 9 of 12 SGM reference strains have the MICs of fidaxomicin at or below 1 µg ml. Fidaxomicin also showed low MIC values for some clinical isolates including complex, complex, , and . Fidaxomicin also has no inducible macrolide resistance in complex in comparison with clarithromycin. Fidaxomicin has high activity against most of the NTM reference strains and some prevalent NTM clinical isolates. This promising finding warrants further investigation on the actions of fidaxomicn and as a potential antibiotic for NTM treatment.
Topics: Anti-Bacterial Agents; Clarithromycin; Clostridioides difficile; Drug Resistance, Bacterial; Fidaxomicin; Humans; Macrolides; Microbial Sensitivity Tests; Mycobacterium; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Rifampin
PubMed: 35708979
DOI: 10.1099/jmm.0.001549