Carbapenems

Creative Biolabs provides customized antibody-antibiotic conjugates (AACs) development services using carbapenems as payloads for targeted immunotherapy with optimized linkers and conjugation strategies. Based on years’ experience of antibody- drug conjugate (ADC) development, we promise to design and synthesize the most suitable antibiotic-linker complex for your AAC project.

Introduction

Carbapenem antibiotics were developed from the carbapenem thienamycin, which is a product derived from Streptomyces cattleya naturally. Carbapenems are used for the treatment of severe, high-risk bacterial infections and multidrug-resistant (MDR) bacterial infections because of its high efficiency. The first carbapenem used in the clinic is Imipenem and it is hydrolyzed in the mammalian kidney by a dehydropeptidase enzyme to a nephrotoxic intermediate, which is co-formulated with the dehydropeptidase inhibitor cilastatin. Imipenem is used in both intravenous and intramuscular formulations.

As another member of carbapenem antibiotics, Meropenem is stable to mammalian dehydropeptidases and does not need co-administration of cilastatin. When compared to imipenem, Meropenem is less efficient in treating gram-positive pathogens infection but more efficient for gram-negative infections. Moreover, It is effective for the treatment of bacterial meningitis. Being similar to meropenem, Doripenem also possesses a spectrum of activity and exhibits greater stability in solution allows the use of prolonged infusions. Other Carbapenems such as Ertapenem, Panipenem/betamipron, Biapenem, and Tebipenem have also been approved for infection treatment.

Fig.1 The chemical structures of the carbapenems ertapenem, meropenem, imipenem and doripenem. The core and tail regions are indicted, as well as functional groups referred to in the text. (Stewart, 2014)

Mode of Action of Carbapenems

The function of carbapenems is to inhibit cell wall synthesis by binding to penicillin-binding protein (PBPs), thus, causing bacterial cell wall defect, bacterial swelling and killing bacteria. Mammals cells without cell wall are not affected by these antibiotics, therefore, these antibiotics with a selective bactericidal effect on bacteria and have little toxicity to the host. It has been proved that the special protein PBPs is the target of this antibiotic on the bacterial serosa. The binding of imipenem to PBP, especially with the strong affinity,  can hinder the synthesis of the cell wall, cause rapid swelling and dissolve bacteria, and the effect is rarely affected by the amount of inoculating bacteria (PH5.5~8.5). Meropenem can quickly penetrate into Enterobacteriaceae and Pseudomonas aeruginosa, and mainly targets PBP2 and PBP3. The targets of Panipenem on Staphylococcus aureus were PBP1 and PBP3, and on Escherichia coli, S. mucilaginosus and Pseudomonas aeruginosa were PBP2.

Fig 2. Mechanism of action of beta-lactam antibiotics.

Carbapenems-based AACs

The AAC is composed of three building blocks: antibiotic payload to kill bacteria, an antibody to target the delivery of the payload to the bacteria, and a linker to attach the payload to the antibody and allow its release once the AAC is internalized by target cells. Carbapenem antibiotics can be used as payload for AACs development to clean infectious bacteria, and a critical specific monoclonal antibody with targeting capability enables the delivery of carbapenems exclusively to the infection site, thereby reducing normal tissues damage. When the mAbs recognize the bacteria, it is internalized via receptor-mediated endocytosis and the carbapenems payload is released to realize the bacteria killing.

Creative Biolabs is well-positioned to develop carbapenems-based AACs in a timely and cost-effective service. Our professional scientists have extensive experience in antibody production, synthetic chemistry, and bio-conjugation, and are committed to providing high-quality services to promote the development of innovative bacterial infection treatments. Please do not hesitate to contact us for more details.
References

1. Stewart, N. K.; et al. "Kinetic and structural requirements for carbapenemase activity in GES-type β-lactamases." Biochemistry 54.2 (2014): 588-597.