Antimicrobial resistance is a global health crisis and few novel antimicrobials have been discovered in recent decades. Natural products, particularly from Streptomyces, are the source of most antimicrobials, yet discovery campaigns focusing on Streptomyces from the soil largely rediscover known compounds. Investigation of understudied and symbiotic sources has seen some success, yet no studies have systematically explored microbiomes for antimicrobials. Here we assess the distinct evolutionary lineages of Streptomyces from insect microbiomes as a source of new antimicrobials through large-scale isolations, bioactivity assays, genomics, metabolomics, and in vivo infection models. Insect-associated Streptomyces inhibit antimicrobial-resistant pathogens more than soil Streptomyces. Genomics and metabolomics reveal their diverse biosynthetic capabilities. Further, we describe cyphomycin, a new molecule active against multidrug resistant fungal pathogens. The evolutionary trajectories of Streptomyces from the insect microbiome influence their biosynthetic potential and ability to inhibit resistant pathogens, supporting the promise of this source in augmenting future antimicrobial discovery.

‘Old’ colistin and polymyxin B are increasingly used as last-line therapy against multidrug-resistant Gram-negative bacteria Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. For intravenous administration, colistin is dosed as its inactive prodrug colistin methanesulfonate (sodium), while polymyxin B is used as its sulfate (active antibacterial). Over the last decade significant progress has been made in understanding their chemistry, pharmacokinetics (PK) and pharmacodynamics (PD). The first scientifically based dosing suggestions are now available for colistin methanesulfonate to generate a desired target steady-state plasma concentration of formed colistin in various categories of critically-ill patients. As simply increasing polymyxin dosage regimens is not an option for optimizing their PK/PD due to nephrotoxicity, combination therapy with other antibiotics has great potential to maximize the efficacy of polymyxins while minimizing emergence of resistance. We must pursue rational approaches to the use of polymyxins and other existing antibiotics through the application of PK/PD principles.

No abstract

New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Candida auris. Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug–resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as C. auris.

APX001 is the prodrug of APX001A, which is a first-in-class small molecule with a unique mechanism of action that inhibits the fungal enzyme Gwt1 in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The goal of the present study was to determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy in the murine disseminated candidiasis model for ( = 5), ( = 5), and ( = 4). MIC values ranged from 0.002 to 0.03 mg/liter for , from 0.008 to 0.06 mg/liter for, and from 0.004 to 0.03 mg/liter for Plasma APX001A pharmacokinetic measurements were performed in mice after oral administration of 4, 16, 64, and 256 mg/kg of body weight APX001. Single-dose pharmacokinetic studies exhibited maximum plasma concentration () values of 0.46 to 15.6 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC) values of 0.87 to 70.0 mg · h/liter, and half-lives of 1.40 to 2.75 h. A neutropenic murine disseminated candidiasis model was utilized for all treatment studies, and drug dosing was by the oral route. Dose fractionation was performed against K1, with total doses ranging from 4 to 1,024 mg/kg/day of APX001 fractionated into regimens of dosing every 3, 6, 8, and 12 h for a 24-h treatment duration. Nonlinear regression analysis was used to determine which PK/PD index best correlated with efficacy on the basis of the reduction in the number of CFU/kidney at 24 h. The 24-h free-drug AUC/MIC ratio (AUC/MIC) was the PK/PD index that best correlated with efficacy (coefficient of determination [] = 0.88). Treatment studies with the remaining strains utilized regimens of 1 to 256 mg/kg of APX001 administered every 6 h for a 24-h duration with and a 96-h study duration with and The dose required to achieve 50% of the maximum effect (ED) and stasis AUC/MIC targets were as follows: for, 3.67 ± 3.19 and 20.60 ± 6.50, respectively; for , 0.38 ± 0.21 and 1.31 ± 0.27, respectively; and for, 7.14 ± 4.54 and 14.67 ± 8.30, respectively. The present studies demonstrated and APX001A and APX001 potency, respectively, against ,, and These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints. The identification of a lower AUC/MIC ratio target for suggests that species-specific susceptibility breakpoints should be explored.