The Azithromycin Pro-Drug CSY5669 Boosts Bacterial Killing While Attenuating Lung Inflammation Associated with Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus

Saris, Anno; Qin, Wanhai; Linge, Christine C. A. van; Reijnders, Tom D.Y.; Florquin, Sandrine; Burnet, Michael; Straß, Simon; Vos, Alex F. de; Poll, Tom van der

doi:10.1128/aac.02298-21

Antimicrob Agents Chemother

2022

DOI: 10.1128/aac.02298-21

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The Azithromycin Pro-Drug CSY5669 Boosts Bacterial Killing While Attenuating Lung Inflammation Associated with Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus

Anno Saris

Wanhai Qin

Christine C. A. van Linge

et al.

Abstract: Antibiotic resistance is a major problem, with methicillin-resistant Staphylococcus aureus (MRSA) being a prototypical example in surgical and community-acquired infections. S. aureus , like many pathogens, is immune evasive and able to multiply within host immune cells. Consequently, compounds that aid host immunity (e.g., by stimulating the host-mediated killing of pathogens) are appealing alternatives or adjuncts to classical antibiotics.

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Cited by 3 publications

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Nanoparticles Combining Host‐Directed Therapeutics and Antibiotics to Boost Bacterial Killing and Overall Survival of Zebrafish Embryos Infected with Mycobacterium Marinum

Schäfer,

Bi,

Fenaroli

et al. 2024

Advanced Therapeutics

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The bacterial pathogen, Mycobacterium tuberculosis (Mtb), remains a leading cause of global morbidity and mortality. Due to the complexity of the infection, the limited efficacy of antibiotics, and the increasing incidence of multi‐drug resistant strains, novel therapeutics are urgently needed. An interesting new approach is to combine antibiotics with treatments that boost the natural ability of host cells to kill the bacteria, so‐called host‐directed therapeutics (HDT). Until now, this approach has not been explored in the context of nanoparticle drug delivery, which may offer several advantages. Here, the HDT drug everolimus and the antibiotic ((S)‐2‐nitro‐6‐((5‐((4‐(trifluoromethoxy)phenyl)ethynyl)pyridin‐2‐yl)methoxy)‐6,7‐dihydro‐5H‐imidazo[2,1‐b][1,3]oxazine, drug D) are focused on. Both of these agents, drug D and everolimus, are encapsulated into one single micelle (PeptoMicelles), resulting in formulation C, and compared with micelles containing only drug D (formulation A) or everolimus (formulation B). They are tested in Mtb‐infected primary macrophages and THP‐1 cells, and in the zebrafish model for TB (Mm infection) using embryo survival analysis. The results show that formulation C, containing drug D and everolimus in one micelle, is significantly more efficient in protecting cells and zebrafish embryos against infection than all other formulations, indicating an improved therapeutic efficacy of HDTs and antibiotics in a single polymeric micelle.

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Nanoparticles Combining Host‐Directed Therapeutics and Antibiotics to Boost Bacterial Killing and Overall Survival of Zebrafish Embryos Infected with Mycobacterium Marinum

Schäfer,

Bi,

Fenaroli

et al. 2024

Advanced Therapeutics

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Design and Synthesis of Novel Antimicrobial Agents

Breijyeh

2023

Antibiotics

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The necessity for the discovery of innovative antimicrobials to treat life-threatening diseases has increased as multidrug-resistant bacteria has spread. Due to antibiotics’ availability over the counter in many nations, antibiotic resistance is linked to overuse, abuse, and misuse of these drugs. The World Health Organization (WHO) recognized 12 families of bacteria that present the greatest harm to human health, where options of antibiotic therapy are extremely limited. Therefore, this paper reviews possible new ways for the development of novel classes of antibiotics for which there is no pre-existing resistance in human bacterial pathogens. By utilizing research and technology such as nanotechnology and computational methods (such as in silico and Fragment-based drug design (FBDD)), there has been an improvement in antimicrobial actions and selectivity with target sites. Moreover, there are antibiotic alternatives, such as antimicrobial peptides, essential oils, anti-Quorum sensing agents, darobactins, vitamin B6, bacteriophages, odilorhabdins, 18β-glycyrrhetinic acid, and cannabinoids. Additionally, drug repurposing (such as with ticagrelor, mitomycin C, auranofin, pentamidine, and zidovudine) and synthesis of novel antibacterial agents (including lactones, piperidinol, sugar-based bactericides, isoxazole, carbazole, pyrimidine, and pyrazole derivatives) represent novel approaches to treating infectious diseases. Nonetheless, prodrugs (e.g., siderophores) have recently shown to be an excellent platform to design a new generation of antimicrobial agents with better efficacy against multidrug-resistant bacteria. Ultimately, to combat resistant bacteria and to stop the spread of resistant illnesses, regulations and public education regarding the use of antibiotics in hospitals and the agricultural sector should be combined with research and technological advancements.

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Dalbavancin Boosts the Ability of Neutrophils to Fight Methicillin-Resistant Staphylococcus aureus

Scutera

Sparti

Comini

et al. 2023

IJMS

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Polymorphonuclear leukocytes (PMNs) are the most important cell type involved in the early nonspecific host response to bacterial pathogens. Staphylococcus aureus has evolved mechanisms to evade immune responses that contribute to its persistence in PMNs, and acquired resistance to several antimicrobials. Additionally, methicillin-resistant S. aureus (MRSA) is one of the most common causes of acute bacterial skin and skin-structure infections (ABSSSIs). Dalbavancin (DBV), a lipoglycopeptide, is indicated for the treatment of ABSSSIs, and has a broad spectrum of action against most microorganisms. Here, we sought to determine the effect of DBV on the neutrophil killing of MRSA and its potential immunomodulating activity. Our results revealed that DBV boosts MRSA killing by acting on both bacteria and PMNs. DBV pre-treatment of PMNs did not change the respiratory burst or degranulation, while an increased trend in neutrophil extracellular traps-associated elastase and in the production of TNFα and CXCL8 was revealed. In parallel, DBV caused a delay in the apoptosis of MRSA-infected neutrophils. In conclusion, we demonstrated a cooperative effect between the antimicrobial properties of PMNs and DBV, thus owing to their immunomodulatory activity. In the choice of the treatment management of serious S. aureus infections, DBV should be considered as an outstanding option since it reinforces PMNs pathogen clearance capability by exerting its effect directly, not only on MRSA but also on neutrophils.

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The Azithromycin Pro-Drug CSY5669 Boosts Bacterial Killing While Attenuating Lung Inflammation Associated with Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus

Cited by 3 publications

References 47 publications

Nanoparticles Combining Host‐Directed Therapeutics and Antibiotics to Boost Bacterial Killing and Overall Survival of Zebrafish Embryos Infected with Mycobacterium Marinum

Nanoparticles Combining Host‐Directed Therapeutics and Antibiotics to Boost Bacterial Killing and Overall Survival of Zebrafish Embryos Infected with Mycobacterium Marinum

Design and Synthesis of Novel Antimicrobial Agents

Dalbavancin Boosts the Ability of Neutrophils to Fight Methicillin-Resistant Staphylococcus aureus

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