The rise and dissemination of glycopeptide antibiotic (GPA)-resistant pathogens in healthcare settings fuel efforts to discover GPAs that can overcome resistance. Members of the type V subclass of GPAs can evade common GPA resistance mechanisms and offer promise as new drug leads. We characterize five new type V GPAs-rimomycin-A/B/C and misaugamycin-A/B-discovered through a phylogeny-guided genome mining strategy coupled with heterologous production using our GPAHex synthetic biology platform. Rimomycin is a heptapeptide similar to kistamicin but includes an
The rise of drug-resistant fungal pathogens, including Candida auris , highlights the urgent need for novel antifungal therapies. We developed a cost-effective platform combining microbial extract prefractionation with rapid MS/MS-bioinformatics-based dereplication to efficiently prioritize new antifungal scaffolds. Screening C. auris and C. albicans revealed novel lipopeptaibiotics, coniotins, from Coniochaeta hoffmannii WAC11161, which were undetectable in crude extracts. Coniotins exhibited potent activity against critical fungal pathogens on the WHO Fungal Priority Pathogens List, including C. albicans , C. neoformans , multidrug-resistant C. auris , and Aspergillus fumigatus , with high selectivity and low resistance potential. Coniotin A targets β-glucan, compromising fungal cell wall integrity, remodelling, and sensitizing C. auris to caspofungin. Identification of a PKS-NRPS biosynthetic gene cluster further enables the discovery of related clusters encoding potential novel lipopeptaibiotics. This study demonstrates the power of natural product prefractionation in uncovering bioactive scaffolds and introduces coniotins as promising candidates for combating multidrug-resistant fungal pathogens.
Abstract Background Probiotic use in preterm infants can mitigate the impact of antibiotic exposure and reduce rates of certain illnesses; however, the benefit on the gut resistome, the collection of antibiotic resistance genes, requires further investigation. We hypothesized that probiotic supplementation of early preterm infants (born < 32-week gestation) while in hospital reduces the prevalence of antibiotic resistance genes associated with pathogenic bacteria in the gut. We used a targeted capture approach to compare the resistome from stool samples collected at the term corrected age of 40 weeks for two groups of preterm infants (those that routinely received a multi-strain probiotic during hospitalization and those that did not) with samples from full-term infants at 10 days of age to identify if preterm birth or probiotic supplementation impacted the resistome. We also compared the two groups of preterm infants up to 5 months of age to identify persistent antibiotic resistance genes. Results At the term corrected age, or 10 days of age for the full-term infants, we found over 80 antibiotic resistance genes in the preterm infants that did not receive probiotics that were not identified in either the full-term or probiotic-supplemented preterm infants. More genes associated with antibiotic inactivation mechanisms were identified in preterm infants unexposed to probiotics at this collection time-point compared to the other infants. We further linked these genes to mobile genetic elements and Enterobacteriaceae , which were also abundant in their gut microbiomes. Various genes associated with aminoglycoside and beta-lactam resistance, commonly found in pathogenic bacteria, were retained for up to 5 months in the preterm infants that did not receive probiotics. Conclusions This pilot survey of preterm infants shows that probiotics administered after preterm birth during hospitalization reduced the diversity and prevented persistence of antibiotic resistance genes in the gut microbiome. The benefits of probiotic use on the microbiome and the resistome should be further explored in larger groups of infants. Due to its high sensitivity and lower sequencing cost, our targeted capture approach can facilitate these surveys to further address the implications of resistance genes persisting into infancy without the need for large-scale metagenomic sequencing.
Macrolide antibiotics, including azithromycin, can reduce under-five mortality rates and treat various infections in children in sub-Saharan Africa. These exposures, however, can select for antibiotic-resistant bacteria in the gut microbiota.
Identification of the nucleotide sequences encoding antibiotic resistance elements and determination of their association with antibiotic resistance are critical to improve surveillance and monitor trends in antibiotic resistance. Current methods to study antibiotic resistance in various environments rely on extensive deep sequencing or laborious culturing of fastidious organisms, both of which are heavily time-consuming operations.
ABSTRACT Mass distribution of azithromycin has been recommended to reduce under-five mortality rates in certain countries in sub-Saharan Africa. Additionally, antibiotic treatment of children with bacterial gastroenteritis holds promise for the prevention of mortality and the optimization of linear growth. However, mass administration and imprudent prescription of antibiotics can select for antibiotic-resistant bacteria in the gut microbiota of children. The long-term implications of this selection are unknown and worrisome. Our previous randomized controlled trial of children hospitalized with severe acute diarrhoeal disease in Botswana evaluated the efficacy of a test-and-treat strategy. Participants randomized to the intervention group who were found to have enterotoxigenic or enteropathogenic E. coli, Shigella, or Campylobacter detectable by a rapid qualitative multiplex PCR assay at admission were treated with azithromycin and those randomized to the control group received supportive treatment (usual care). Stool samples were collected at baseline and at 60 days. In this current study, DNA from 136 stool samples was enriched and sequenced to detect changes in the resistome, otherwise known as the collection of antibiotic resistance genes. At baseline, the gut microbiota of these children contained a diverse complement of azithromycin resistance genes that increased in prevalence in both treatment groups by 60 days. Certain 23S rRNA methyltransferases were associated with other resistance genes and mobile genetic elements, highlighting the potential for the transfer of macrolide resistance in the gut microbiome. There were other minor changes in non-azithromycin resistance genes; however, the trends were not specific to the antibiotic-treated children. In conclusion, a three-day azithromycin treatment for diarrhoea for young children in Botswana did not increase the prevalence of azithromycin-specific antibiotic resistance genes at 60 days. The gut microbiota of these children appeared primed for macrolide resistance, and repeated exposures may further select resistant bacteria.
Increasing multidrug resistance in Neisseria gonorrheae is a growing public health crisis. Resistance to the last line therapies, cephalosporins and azithromycin, are of particular concern, fueling the need to discover new treatments. Here, we identified the phosphoglycolipid moenomycin from a screen of microbial natural products against drug-resistant N. gonorrheae as a potent antigonococcal agent. Moenomycin demonstrates excellent activity (MIC = 0.004–0.03 μg/mL) against a variety of multidrug-resistant N. gonorrheae. Importantly, moenomycin, thought to be a Gram-positive specific antibiotic, penetrates the Gram-negative gonococcal outer membrane. Moenomycin causes intracellular accumulation of peptidoglycan precursors, cell blebbing, and rupture of the cell envelope, all consistent with cell wall biosynthesis inhibition. Serial bacterial exposure to moenomycin for 14 days revealed slow development of resistance (MICDay14 = 0.03–0.06 μg/mL), unlike the clinically used drug azithromycin. Our results offer the potential utility of moenomycin as a lead for antigonococcal therapeutic candidates and warrant further investigation.
