A microbial natural product fractionation library screen with HRMS/MS dereplication identifies new lipopeptaibiotics against Candida auris.

The rise of drug-resistant fungal pathogens, including , 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 and revealed novel lipopeptaibiotics, coniotins, from WAC11161, which were undetectable in crude extracts.

Butyrolactol A is a phospholipid flippase inhibitor that potentiates the bioactivity of caspofungin against resistant fungi.

Fungal infections cause millions of deaths annually and are challenging to treat due to limited antifungal options and increasing drug resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while , a notorious global threat, is also increasingly resistant. We performed a natural product extract screen for rescue of the activity of the echinocandin caspofungin against H99, identifying butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including .

Minimal Impact on the Resistome of Children in Botswana After Azithromycin Treatment for Acute Severe Diarrheal Disease.

Background: Macrolide antibiotics, including azithromycin, can reduce under 5 years of age 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.

Methods: Our previous randomized controlled trial (RCT) of a rapid-test-and-treat strategy for severe acute diarrheal disease in children in Botswana included an intervention (3-day azithromycin dose) group and a control group that received supportive treatment.

Capturing the antibiotic resistome of preterm infants reveals new benefits of probiotic supplementation.

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.

Phylogeny-Informed Synthetic Biology Reveals Unprecedented Structural Novelty in Type V Glycopeptide Antibiotics.

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.

The Pseudomonas aeruginosa homeostasis enzyme AlgL clears the periplasmic space of accumulated alginate during polymer biosynthesis.

Pseudomonas aeruginosa is an opportunistic human pathogen and a leading cause of chronic infection in the lungs of individuals with cystic fibrosis. After colonization, P. aeruginosa often undergoes a phenotypic conversion to mucoidy, characterized by overproduction of the alginate exopolysaccharide.

A Screen of Natural Product Extracts Identifies Moenomycin as a Potent Antigonococcal Agent.

Increasing multidrug resistance in 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 as a potent antigonococcal agent.

GPAHex-A synthetic biology platform for Type IV-V glycopeptide antibiotic production and discovery.

Glycopeptide antibiotics (GPAs) are essential for the treatment of severe infectious diseases caused by Gram-positive bacteria. The emergence and spread of GPA resistance have propelled the search for more effective GPAs. Given their structural complexity, genetic intractability, and low titer, expansion of GPA chemical diversity using synthetic or medicinal chemistry remains challenging.

Capturing the Resistome: a Targeted Capture Method To Reveal Antibiotic Resistance Determinants in Metagenomes.

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. An accurate and sensitive method to identify both rare and common resistance elements in complex metagenomic samples is needed.

Antimicrobial Resistance and Respiratory Infections.

Since their introduction into health care and clinical practice in the early 20th century, antibiotics have revolutionized medicine. Alarmingly, these drugs are increasingly threatened by bacteria that have developed a broad diversity of resistance mechanisms. Antibiotic resistance can be transferred between bacteria, often on mobile genetic elements; be acquired from the environment; or arise through mutation because of selective pressures of the drugs themselves.