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Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class of antibiotics 1 . Virginiamycin acetyltransferase (Vat) enzymes are resistance proteins that provide protection against streptogramins 2 , potent antibiotics against Gram-positive bacteria that inhibit the bacterial ribosome 3 . Owing to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome the resistance conferred by Vat enzymes have not been previously developed 2 . Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with extensive structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogues to the bacterial ribosome at high resolution, revealing binding interactions that extend into the peptidyl tRNA-binding site and towards synergistic binders that occupy the nascent peptide exit tunnel. One of these analogues has excellent activity against several streptogramin-resistant strains of Staphylococcus aureus , exhibits decreased rates of acetylation in vitro, and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms. Modular synthesis and structural biology are used to design and characterize group A streptogramin antibiotics, one of which has activity against streptogramin-resistant strains and demonstrates efficacy in a mouse model of bacterial infection.

Objective The purpose of this study is a new update on the resistance profile, Macrolide–Lincosamide–Streptogramin B resistance mechanisms and biofilm formation in the Staphylococcus aureus isolated from health care workers (HCWs) nasal carriage at a children’s teaching hospital in Babol (Northern Iran). Results A total of 143 non-repetitive nasal swab samples were collected from volunteers, where 53.8% (n; 77/143) were HCWs, 33.6% (n; 48/143) medical students, and 12.6% (n; 18/143) resident students. The prevalence of nasal carriers of S. aureus was 22.4% (n; 32/143), among them, 40.6% (n; 13/32) were identified as methicillin-resistant Staphylococcus aureus (MRSA( carriers. Antimicrobial susceptibility testing showed that erythromycin (68.8%, n; 22/32) and ciprofloxacin (15.6%, n; 5/32) had the highest and lowest resistance rate, respectively. The frequency of resistance genes in the strains was as follows; ermC (n; 17/32, 53.1%), ermA (n; 11/32, 34.4%), ermB (n; 6/32, 18.7%), ereA (n; 3/32, 9.4%). Moreover, 50.0% (n; 16/32), 28.1% (n; 9/32) and 21.8% (n; 7/32) of isolates were strongly, weakly and moderately biofilm producer, respectively. Macrolides-lincosamides-streptogramins B (MLSB) antibiotic resistance among S. aureus isolates from HCWs nasal carriage have found significant prevalence rates throughout the globe. It is crucial to remember that the development of biofilms and MLS B antibiotic resistance are both dynamic processes.

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern 1 . For more than five decades, the search for new antibiotics has relied heavily on the chemical modification of natural products (semisynthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semisynthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings 2 . Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, which we name iboxamycin. Iboxamycin is effective against ESKAPE pathogens including strains expressing Erm and Cfr ribosomal RNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native bacterial ribosome, as well as with the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including a displacement of the m 2 6 A 2058 nucleotide upon antibiotic binding. Iboxamycin is orally bioavailable, safe and effective in treating both Gram-positive and Gram-negative bacterial infections in mice, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of increasing resistance. Structure-guided design and component-based synthesis are used to produce iboxamycin, a novel ribosome-binding antibiotic with potent activity against Gram-positive and Gram-negative bacteria.

Background Gram-positive Streptococci is a huge group of different species that are classified based on its hemolytic effect besides the C-substance in the cell wall. This study focuses on the investigation of the prevalence and genetic basis of resistance to macrolides, lincosamides, and streptogramins (MLS) in α- and β-hemolytic Streptococci . Methods Streptococcal isolates were identified and their resistance was assessed to MLS antibiotics through phenotypic analysis and genotypic screening of resistance genes. Isolates were also tested for susceptibility to antiseptics/disinfectants. The correlation between high MLS antibiotic resistance and reduced susceptibility to biocides was assessed. Efflux pump activity in the most resistant isolates (to both MLS antibiotics and biocides) was investigated. Results The susceptibility testing indicates an increasing resistance to MLS, particularly macrolides (erythromycin, azithromycin, and clarithromycin) and lincomycin. By screening the resistance, the most predominant phenotype is the constitutive (cMLS) one, while the erm genes, particularly ermB , are the most detected genotype. Furthermore, the esterase-encoding gene ereA is widely distributed in the streptococcal isolates. By evaluating the minimum inhibitory concentrations (MICs) to different biocides, there was a strong relation between the increased MIC values to both MLS antibiotics and tested biocides. This can be attributed mainly to the transferable ermB gene and the enhanced bacterial efflux. Conclusions A significant correlation exists between reduced biocide susceptibility and resistance to MLS antibiotics. Elevated efflux pump activity in MLS-resistant isolates suggests efflux mechanisms may contribute to dual resistance to antibiotics and biocides. However, cross-resistance is primarily driven by the horizontally transferable ermB gene, which confers resistance by targeting the 50S ribosomal subunit.

Background This study aims to explore the antibacterial activity of cethromycin against Staphylococcus aureus ( S. aureus ), and its relationship with multilocus sequence typing (MLST), erythromycin ribosomal methylase ( erm ) genes and macrolide-lincosamide-streptogramin B (MLSB) phenotypes of S. aureus. Results The minimum inhibitory concentrations (MICs) of cethromycin against 245 S. aureus clinical isolates ranged from 0.03125 to ≥ 8 mg/L, with the resistance of 38.8% in 121 methicillin-resistant S. aureus (MRSA). This study also found that cethromycin had strong antibacterial activity against S. aureus , with the MIC ≤ 0.5 mg/L in 55.4% of MRSA and 60.5% of methicillin-sensitive S. aureus (MSSA), respectively. The main MLSTs of 121 MRSA were ST239 and ST59, and the resistance of ST239 isolates to cethromycin was higher than that in ST59 isolates ( P  = 0.034) . The top five MLSTs of 124 MSSA were ST7, ST59, ST398, ST88 and ST120, but there was no difference in the resistance of MSSA to cethromycin between these STs. The resistance of ermA isolates to cethromycin was higher than that of ermB or ermC isolates in MRSA ( P  = 0.016 and 0.041, respectively), but the resistance of ermB or ermC isolates to cethromycin was higher than that of ermA isolates in MSSA ( P  = 0.019 and 0.026, respectively). The resistance of constitutive MLSB (cMLSB) phenotype isolates to cethromycin was higher than that of inducible MLSB (iMLSB) phenotype isolates in MRSA ( P  < 0.001) or MSSA ( P  = 0.036). The ermA , ermB and ermC genes was mainly found in ST239, ST59 and ST1 isolates in MRSA, respectively. Among the MSSA, the ermC gene was more detected in ST7, ST88 and ST120 isolates, but more ermB genes were detected in ST59 and ST398 isolates. The cMLSB phenotype was more common in ST239 and ST59 isolates of MRSA, and was more frequently detected in ST59, ST398, and ST120 isolates of MSSA. Conclusion Cethromycin had strong antibacterial activity against S. aureus . The resistance of MRSA to cethromycin may had some clonal aggregation in ST239. The resistance of S. aureus carrying various erm genes or MLSB phenotypes to cethromycin was different.

Background Wastewater treatment plants (WWTPs) are recognized as hotspots for horizontal gene transfer (HGT) of antibiotic resistance genes (ARGs). Despite our understanding of the composition and distribution of ARGs in WWTPs, the genetic location, host, and fate of ARGs remain largely unknown. Results In this study, we combined Oxford Nanopore and Illumina metagenomics sequencing to comprehensively uncover the resistome context of influent, activated sludge, and effluent of three WWTPs and simultaneously track the hosts of the ARGs. The results showed that most of the ARGs detected in all compartments of the WWTPs were carried by plasmids. Transposons and integrons also showed higher prevalence on plasmids than on the ARG-carrying chromosome. Notably, integrative and conjugative elements (ICEs) carrying five types of ARGs were detected, and they may play an important role in facilitating the transfer of ARGs, particularly for tetracycline and macrolide-lincosamide-streptogramin (MLS). A broad spectrum of ARGs carried by plasmids (29 subtypes) and ICEs (4 subtypes) was persistent across the WWTPs. Host tracking showed a variety of antibiotic-resistant bacteria in the effluent, suggesting the high potential for their dissemination into receiving environments. Importantly, phenotype-genotype analysis confirmed the significant role of conjugative plasmids in facilitating the survival and persistence of multidrug-resistant bacteria in the WWTPs. At last, the consistency in the quantitative results for major ARGs types revealed by Nanopore and Illumina sequencing platforms demonstrated the feasibility of Nanopore sequencing for resistome quantification. Conclusion Overall, these findings substantially expand our current knowledge of resistome in WWTPs, and help establish a baseline analysis framework to study ARGs in the environment.

Because poor sanitation is hypothesized as a major direct and indirect pathway of exposure to antimicrobial resistance genes (ARGs), we sought to determine a) the prevalence of and b) environmental risk factors for gut carriage of key ARGs in a pediatric cohort at high risk of enteric infections due to poor water, sanitation, and hygiene (WASH) conditions. We investigated ARGs in stool from young children in crowded, low-income settlements of Maputo, Mozambique, and explored potential associations with concurrent enteric pathogen carriage, diarrhea, and environmental risk factors, including WASH. We collected stool from 120 children <14 months old and tested specimens via quantal, multiplex molecular assays for common bacterial, viral, and protozoan enteric pathogens and 84 ARGs encoding potential resistance to 7 antibiotic classes. We estimated associations between ARG detection (number and diversity detected) and concurrently-measured enteric pathogen carriage, recently-reported diarrhea, and risk factors in the child's living environment. The most commonly-detected ARGs encoded resistance to macrolides, lincosamides, and streptogramins (100% of children); tetracyclines (98%); β-lactams (94%), aminoglycosides (84%); fluoroquinolones (48%); and vancomycin (38%). Neither concurrent diarrhea nor measured environmental (including WASH) conditions were associated with ARG detection in adjusted models. Enteric pathogen carriage and ARG detection were associated: on average, 18% more ARGs were detected in stool from children carrying bacterial pathogens than those without (adjusted risk ratio (RR): 1.18, 95% confidence interval (CI): 1.02, 1.37), with 16% fewer ARGs detected in children carrying parasitic pathogens (protozoans, adjusted RR: 0.84, 95% CI: 0.71, 0.99). We observed gut ARGs conferring potential resistance to a range of antibiotics in this at-risk cohort that had high rates of enteric infection, even among children <14 months-old. Gut ARGs did not appear closely correlated with WASH, though environmental conditions were generally poor. ARG carriage may be associated with concurrent carriage of bacterial enteric pathogens, suggesting indirect linkages to WASH that merit further investigation.

Given the increase in antibiotic-resistant bacteria, alongside the alarmingly low rate of newly approved antibiotics for clinical usage, we are on the verge of not having effective treatments for many common infectious diseases. Historically, antibiotic discovery has been crucial in outpacing resistance and success is closely related to systematic procedures—platforms—that have catalyzed the antibiotic golden age, namely the Waksman platform, followed by the platforms of semi-synthesis and fully synthetic antibiotics. Said platforms resulted in the major antibiotic classes: aminoglycosides, amphenicols, ansamycins, beta-lactams, lipopeptides, diaminopyrimidines, fosfomycins, imidazoles, macrolides, oxazolidinones, streptogramins, polymyxins, sulphonamides, glycopeptides, quinolones and tetracyclines. During the genomics era came the target-based platform, mostly considered a failure due to limitations in translating drugs to the clinic. Therefore, cell-based platforms were re-instituted, and are still of the utmost importance in the fight against infectious diseases. Although the antibiotic pipeline is still lackluster, especially of new classes and novel mechanisms of action, in the post-genomic era, there is an increasingly large set of information available on microbial metabolism. The translation of such knowledge into novel platforms will hopefully result in the discovery of new and better therapeutics, which can sway the war on infectious diseases back in our favor.

Heterologous expression of the G231L variant of VioA into 16 strains of marine-derived Streptomyces, combined with bioactivity tracking, leads to the activation of seven antibiotic streptogramins (1–7) in Streptomyces sp. OUC20-O. Among these, compound 1, named linstreptogramin, is a new compound with an unusual linear streptogramin skeleton. The planar structure and stereochemistry of compound 1 were established based on extensive MS and NMR spectroscopic analyses, together with ECD calculations. In the antibacterial activity evaluation, compounds 1–4 showed significant growth inhibition against the multidrug-resistant Enterococcus faecium CCARM 5203 with MIC values of 0.2–1.6 µg/mL, which are comparable to the positive control vancomycin.

Mycoplasma genitalium is an important sexually transmitted pathogen responsible for both male and female genital tract disease. Appreciation of its significance in human disease has been hampered by its slow growth in culture, difficulty in isolating it, and lack of commercial molecular-based tests for rapid detection. Comparatively few in vitro data on antimicrobial susceptibility are available due to the scarcity of clinical isolates and difficulty in performing susceptibility tests to determine minimum inhibitory concentrations for M. genitalium. Antimicrobial agents that inhibit protein synthesis such as macrolides, along with fluoroquinolones that inhibit DNA replication, have been the treatments of choice for M. genitalium infections. Even though international guidelines recommend azithromycin as first-line treatment, rapid spread of macrolide resistance as well as emergence of quinolone resistance has occurred. Increasing rates of treatment failure have resulted in an urgent need for new therapies and renewed interest in other classes such as aminocyclitols, phenicols, and streptogramins as treatment alternatives. Limited data for new investigational antimicrobials such as the ketolide solithromycin suggest that this drug may eventually prove useful in management of some resistant M. genitalium infections, although it is not likely to achieve cure rates >80% in macrolide-resistant strains, in a similar range as recently reported for pristinamycin. However, agents with completely new targets and/or mechanisms that would be less likely to show cross-resistance with currently available drugs may hold the greatest promise. Lefamulin, a pleuromutilin, and new nonquinolone topoisomerase inhibitors are attractive possibilities that require further investigation.