The dynamics of Staphylococcal infection and their treatment with antibiotics and bacteriophage in the Galleria mellonella model system
Berryhill, Brandon A
;
Gil-Gil, Teresa
;
Witzany, Christopher
, et al.
bioRxiv,2024.
DOI:
10.1101/2024.08.23.609294
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Abstract: Critical to our understanding of infections and their treatment is the role the innate immune system plays in controlling bacterial pathogens. Nevertheless, many in vivo systems are made or modified such that they do not have an innate immune response. Use of these systems denies the opportunity to examine the synergy between the immune system and antimicrobial agents. In this study we demonstrate that the larva of Galleria mellonella is an effective in vivo model for the study of the population and evolutionary biology of bacterial infections and their treatment. To do this we test three hypotheses concerning the role of the innate immune system during infection. We show: i) sufficiently high densities of bacteria are capable of saturating the innate immune system, ii) bacteriostatic drugs and bacteriophages are as effective as bactericidal antibiotics in preventing mortality and controlling bacterial densities, and iii) minority populations of bacteria resistant to a treating antibiotic will not ascend. Using a highly virulent strain of Staphylococcus aureus and a mathematical computer-simulation model, we further explore how the dynamics of the infection within the short term determine the ultimate infection outcome. We find that excess immune activation in response to high densities of bacteria leads to a strong but short-lived immune response which ultimately results in a high degree of mortality. Overall, our findings illustrate the utility of the G. mellonella model system in conjunction with established in vivo models in studying infectious disease progression and treatment.
Keywords:
Staphylococcus aureus ;
Galleria mellonella ;
innate immunity ;
infection dynamics ;
model system
Purchased from AmBeed:
165800-03-3
Design and synthesis of novel arylurea derivatives of aryloxy (1-phenylpropyl) alicyclic diamines with antimicrobial activity against multidrug-resistant Gram-positive bacteria
Canale, Vittorio
;
Czekajewska, Joanna
;
Klesiewicz, Karolina
, et al.
Eur. J. Med. Chem.,2023,251,115224.
DOI:
10.1016/j.ejmech.2023.115224
PubMed ID:
36958177
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Abstract: The alarming increase in the resistance of bacteria to the currently available antibiotics necessitates the development of new effective antimicrobial agents that are active against bacterial pathogens causing major public health problems. For this purpose, our inhouse libraries were screened against a wide panel of clin. relevant Gram-pos. and Gram-neg. bacteria, based on which compound I was selected for further optimization. Synthetic efforts in a group of arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines, followed with an in vitro evaluation of the activity against multidrug-resistant strains identified compound 44 (1-(3-chlorophenyl)-3-(1-{3-phenyl-3-[3-(trifluoromethyl)phenoxy] propyl}piperidin-4-yl)urea). Compound 44 showed antibacterial activity against Gram-pos. bacteria including fatal drug-resistant strains i.e., Staphylococcus aureus (methicillin-resistant, MRSA; vancomycin-intermediate, VISA) and Enterococcus faecium (vancomycin-resistant, VREfm) at low concentrations (0.78-3.125 μg/mL) comparable to last resort antibiotics (i.e., vancomycin and linezolid). It is also potent against biofilm-forming S. aureus and Staphylococcus epidermidis (including linezolid-resistant, LRSE) strains, but with no activity against Gram-neg. bacteria (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa). Compound 44 showed strong bactericidal properties against susceptible and drug-resistant Gram-pos. bacteria. Depolarization of the bacterial cytoplasmic membrane induced by compound 44 suggests a dissipation of the bacterial membrane potential as its mechanism of antibacterial action. The high antimicrobial activity of compound 44, along with its selectivity over mammalian cells (lung MCR-5 and skin BJ fibroblast cell lines) and no hemolytic properties toward horse erythrocytes, proposes arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines for development of novel antibacterial agents.
Keywords:
Arylurea derivatives ;
Antibacterial properties ;
Anti-MRSA activity ;
Anti-VRE activity ;
Anti-LRSE activity ;
Depolarization of bacterial cell membrane
Purchased from AmBeed:
122536-76-9 ;
936-59-4 ;
135632-53-0 ;
404-71-7 ;
73874-95-0 ;
372-20-3 ;
98-17-9 ;
402-45-9 ;
57260-71-6 ;
122536-77-0 ;
444-30-4 ;
165800-03-3 ;
150-19-6 ;
1195-45-5 ;
2909-38-8 ;
165800-03-3
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 alicyclic diamines with antimicrobial activity against multidrug-resistant Gram-positive bacteria.jpg)
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