作者: de Block, Tessa ; Baranchyk, Yuliia ; Gestels, Zina ; De Baetselier, Irith ; Manoharan-Basil, Sheeba Santhini ; Van Den Bossche, Dorien ; Kenyon, Chris ; Abdellati, Saïd

Background The emergence of ceftriaxone-resistant Neisseria gonorrhoeae poses a significant threat to existing treatment regimens. Our study aimed to assess the efficacy of antimicrobials that could be combined with ceftriaxone to reduce the probability of ceftriaxone resistance emerging and spreading in N. gonorrhoeae. Methods and Results Broth microdilution was used to determine the minimal inhibitory concentrations (MICs) for a panel of ceftriaxone-resistant (WHO X, Y, Z) and ceftriaxone-susceptible (WHO L, N, P) N. gonorrhoeae WHO reference strains for the following antimicrobials: ceftriaxone, doxycycline, azithromycin, zoliflodacin, fosfomycin, pristinamycin, ramoplanin, gentamicin and NAI-107. The MICs for zoliflodacin and pristinamycin for all strains were lower than or equal to the available breakpoints. A checkerboard assay was used to determine the drug-drug combination effect, which showed either an indifferent or an additive effect for all the combinations tested with ceftriaxone. Conclusions The low MICs of zoliflodacin and pristinamycin for the three ceftriaxone-resistant strains suggest that these antimicrobials could be used as partner drugs with ceftriaxone to reduce the probability of ceftriaxone resistance spreading in areas with a high prevalence of ceftriaxone resistance.

2024-06-28·Journal of Natural Products

Facile Halogenation of Antimicrobial Peptides As Demonstrated by Producing Bromotryptophan-Labeled Nisin Variants with Enhanced Antimicrobial Activity

Article

作者: Broos, Jaap ; Guo, Longcheng ; Kuipers, Oscar P

Antimicrobial peptides (AMPs) have raised significant interest, forming a potential new class of antibiotics in the fight against multi-drug-resistant bacteria. Various AMPs are ribosomally synthesized and post-translationally modified peptides (RiPPs). One post-translational modification found in AMPs is the halogenation of Trp residues. This modification has, for example, been shown to be critical for the activity of the potent AMP NAI-107 from Actinoallomurus. Due to the importance of organohalogens, establishing methods for facile and selective halogen atom installation into AMPs is highly desirable. In this study, we introduce an expression system utilizing the food-grade strain Lactococcus lactis, facilitating the efficient incorporation of bromo-Trp (BrTrp) into (modified) peptides, exemplified by the lantibiotic nisin with a single Trp residue or analogue incorporated at position 1. This provides an alternative to the challenges posed by halogenase enzymes, such as poor substrate selectivity. Our method yields expression levels comparable to that of wild-type nisin, while BrTrp incorporation does not interfere with the post-translational modifications of nisin (dehydration and cyclization). One brominated nisin variant exhibits a 2-fold improvement in antimicrobial activity against two tested pathogens, including a WHO priority pathogen, while maintaining the same lipid II binding and bactericidal activity as wild-type nisin. The work presented here demonstrates the potential of this methodology for peptide halogenation, offering a new avenue for the development of diverse antimicrobial products labeled with BrTrp.

2023-12-12·Microbiology Spectrum

Microbisporicin (NAI-107) protects Galleria mellonella from infection with Neisseria gonorrhoeae

Article

作者: Gestels, Zina ; Martin, Anandi ; Abdellati, Said ; De Baetselier, Irith ; Manoharan-Basil, Sheeba Santhini ; Gabant, Philippe ; Hofkens, Nele ; Kenyon, Christopher

ABSTRACT Due to the increasing incidence of antibiotic-resistant bacterial pathogens, the need for the development of alternative compounds is of utmost importance. Bacteriocins are considered a promising alternative to antibiotics. In this study, we determined the in vitro activities of 65 bacteriocins from the PARAGEN collection along with microbisporicin (NAI-107) against 14 WHO reference isolates of Neisseria gonorrhoeae , one isolate of Neisseria meningitidis , and four commensal Neisseria spp. The initial screening of the bacteriocins was carried out using a spot-on-lawn assay wherein 12 bacteriocins (12/66) showed a zone of inhibition against the WHO-P N. gonorrhoeae isolate. Four bacteriocins (4/12), Garvicin KS (GarKS) (ABC), lacticin (lcn) Q, lcn Z, and NAI-107, demonstrated higher activity, and minimum inhibitory concentrations (MICs) using agar dilutions were determined for 19 Neisseria spp. GarKS (ABC), lcn Q, and lcn Z had an MIC range of 4–16 µg/mL, whereas NAI-107 had an MIC range of <0.25 to 2 µg/mL. Using an in vivo Galleria mellonella model, we determined the efficacy of GarKS (ABC), lcn Z, and NAI-107. GarKS (ABC) and lcn Z displayed no in vivo toxicity but showed no in vivo activity against WHO-P N. gonorrhoeae . In contrast, NAI-107 was as effective as ceftriaxone and significantly increased the survival rate of WHO-P N. gonorrhoeae -infected G. mellonella larvae. In conclusion, NAI-107 exhibited potent in vitro and in vivo activities against N. gonorrhoeae . To our knowledge, this is the first study to demonstrate that NAI-107 possesses anti-gonococcal activity in vivo . IMPORTANCE We screened 66 bacteriocins to see if they exhibited anti-gonococcal activity. We found 12 bacteriocins with anti-gonococcal effects, and 4 bacteriocins showed higher anti-gonococcal activity. Three bacteriocins, lacticin Z, lacticin Q, and Garvicin KS (ABC), showed in vitro anti-gonococcal activity but no in vivo inhibitory effects against the Neisseria gonorrhoeae (WHO-P) isolate. On the other hand, NAI-107 showed in vivo anti-gonococcal activity. The findings suggest that NAI-107 is a promising alternative to treat gonorrhea infections.

100 项与 NAI-107 相关的药物交易

登录后查看更多信息