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Ceftazidime/avibactam combined with amikacin or gentamicin resulted in undetectable counts 50h sooner than ceftazidime/avibactam monotherapy against KPC-Kp with aac(6')-Ib'. Ceftazidime/avibactam monotherapy failed to eradicate KPC-Kp with aac(6')-Ib and a combination with gentamicin led to undetectable counts 70h sooner than with amikacin. A one-time aminoglycoside dose with ceftazidime/avibactam provided similar killing to aminoglycosides dosed for 7 days. In the mouse pneumonia model (n=1 isolate), gentamicin and ceftazidime/avibactam achieved a 6.0 log10CFU/lung reduction at 24h, which was significantly greater than either monotherapy (P less then 0.005). Aminoglycosides in combination with ceftazidime/avibactam were promising for KPC-Kp infections; this was true even for a one-time aminoglycoside dose. Selecting aminoglycosides based on AME genes or susceptibilities can improve the pharmacodynamic activity of the combination.Drug resistance is a worldwide problem affecting all pathogens. The human fungal pathogen Aspergillus fumigatus coexists in the environment with other fungi targeted by crop protection compounds being unintentionally exposed to the selective pressure of multiple antifungal classes leading to the selection of resistant strains. A. fumigatus azole resistant isolates are emerging in both the clinical and environmental setting. Since their approval, azole drugs have dominated the clinical treatment for aspergillosis infections, and the agriculture fungicide market. However, other antifungal classes are used for crop protection including benzimidazoles (MBC), strobilurins (QoIs) and succinate dehydrogenase inhibitors (SDHIs). Mutations responsible for resistance to these fungicides have been widely researched in plant pathogens, but it has not been explored in A. fumigatus. In this work, the genetic basis underlying resistance to MBCs, QoIs and SDHIs were studied in azole susceptible and resistant A. fumigatus strains. E198A/Q and F200Y mutations in the β-tubulin conferred resistance to MBCs, G143A and F129L substitutions in the Cytochrome b to QoIs and H270R/Y mutations in SdhB to SDHIs. Characterization of the susceptibility to azoles showed a correlation between strains resistant to these fungicides and the ones with TR-based azole resistance mechanisms. Whole genome sequencing analysis showed a genetic relationship among fungicide multi resistant strains, which grouped together into subclusters that only included strains carrying the TR-based azole resistance mechanisms, indicating a common ancestor/evolution pattern and confirming the environmental origin of this type of azole resistant A. fumigatus.Antibiotic resistance genes exist naturally in various environments far from human usage. Here, we investigated multidrug-resistant Klebsiella pneumoniae, a common pathogen of chimpanzees and humans. We screened antibiotic-resistant K. pneumoniae from 48 chimpanzee stools and 38 termite mounds (N=415 samples) collected in protected areas in Senegal. The microsatellite method was used to identify chimpanzee individuals (N=13). Whole genome sequencing was performed on K. pneumoniae complex isolates to identify antibiotic-resistant genes and characterize clones. We found a high prevalence of carbapenem-resistant K. pneumoniae among chimpanzee isolates (18/48 samples from 7/13 individuals) and ceftriaxone resistance among both chimpanzee individuals (19/48) and termite mounds (7/415 termites and 3/38 termite mounds). The blaOXA-48 and the blaKPC-2 genes were carried by international pOXA-48 and pKPC-2 plasmids respectively. The ESBL plasmid carried blaCTX-M-15, blaTEM-1B and blaOXA-1 genes. Genome sequencing of 56 isolates identified two major clones associated with hospital-acquired infections of K. pneumoniae (ST307 and ST147) in chimpanzees and termites, suggesting circulation of strains between the two species, as chimpanzees feed on termites. The source and selection pressure of these clones in this environment need to be explored.Nafithromycin (13 WCK 4873) is a novel lactone ketolide under clinical development as an orally administrated antibiotic for treatment of community acquired pneumonia (CAP) caused by Streptococcus pneumoniae, Hemophilus influenzae, Moraxella catarrhalis, and methicillin susceptible Staphylococcus aureus.….Sporotrichosis has become an important zoonosis in Brazil and Sporothrix brasiliensis is the primary species transmitted by cats. see more Improvement of animal treatment will help control and limit the spread and geographic expansion of sporotrichosis. Accordingly, buparvaquone, an antiprotozoal hydroxynaphthoquinone agent marketed as Butalex®, was evaluated in vitro and in vivo against feline-borne isolates of S. brasiliensis. Buparvaquone inhibited in vitro fungal growth at concentrations 4-fold lower than itraconazole (the first-choice antifungal used for sporotrichosis) and was 408 times more selective for S. brasiliensis than mammalian cells. Yeasts treated with a subinhibitory concentration of buparvaquone exhibited mitochondrial dysfunction, ROS and neutral lipid accumulation, and impaired plasma membranes. Also, scanning electron microscopy images revealed buparvaquone altered cell wall integrity and induced cell disruption. In vivo experiments in a Galleria mellonella model revealed that buparvaquone (single dose of 5 mg/kg) is more effective than itraconazole against infections with S. brasiliensis yeasts. Combined, our results indicate that buparvaquone has a great in vitro and in vivo antifungal activity against S. brasiliensis, revealing the potential application of this drug as an alternative treatment for feline sporotrichosis.Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, harbors a branched electron transport chain preventing the bactericidal action of cytochrome bc1 inhibitors (e.g. TB47). Here, we investigated, using luminescent mycobacterial strains, the in vitro combination activity of cytochrome bc1 inhibitors and nitric oxide (NO) donors including pretomanid (PMD) and explored the mechanisms of combination activity. The TB47 and PMD combination quickly abolished the light emission of luminescent bacilli, as was the case for the combination of TB47 and aurachin D, a putative cytochrome bd inhibitor. The TB47 and PMD combination inhibited Mtb oxygen consumption, decreased ATP levels, and had a delayed bactericidal effect. The NO scavenger carboxy-PTIO prevented the bactericidal activity of the drug combination, suggesting the requirement for NO. In addition, cytochrome bc1 inhibitors were largely bactericidal when administered with DETA NONOate, another NO donor. Proteomic analysis revealed that the cotreated bacilli had a compromised expression of the dormancy regulon proteins, PE/PPE proteins and proteins required for the biosynthesis of several cofactors, including mycofactocin.