Penicillin Derivatives

Creative Biolabs has over a decade of experience in linker-payload design and synthesis, and now we provide customized penicillin derivatives-linker synthesis service to fit your bio-conjugation strategies.

Introduction

Penicillin was discovered by Scottish scientist Alexander Fleming in 1928. Its first use for treating infections was in 1942. Penicillin antibiotics were the first effective medication against infections caused by staphylococci and streptococci. There are several enhanced penicillin families which are also effective against additional bacteria, including the antistaphylococcal penicillins, aminopenicillins, and the antipseudomonal penicillins. All of them are derived from Penicillium fungi. The term “penam” is used to depict the common core skeleton of the penicillins. This core with the molecular formula R-C9H11N2O4S, in which R is the variable side chain that differentiates the penicillins from one another. The critical structural feature of the penicillins is the four-membered β-lactam ring, which is crucial for penicillin's antibacterial activity. The β-lactam ring is fused to a five-membered thiazolidine ring. The fusion of these two rings endows the β-lactam ring to with enhanced activity when compared to monocyclic β-lactams, that’s because the two fused rings distort the β-lactam amide bond, thus remove the resonance stabilization normally found in these chemical bonds.

Mode of Action of Penicillin Derivatives

Bacteria need to remodel their peptidoglycan cell walls constantly, simultaneously building and breaking down portions of the cell wall during they grow and divide. Penicillin/penicillin derivatives antibiotics inhibit the formation of peptidoglycan cross-links in the bacterial cell wall, which is achieved through binding of the four-membered β-lactam ring of penicillin to the enzyme DD-transpeptidase. As a result, DD-transpeptidase cannot catalyze the formation of these cross-links, leading to an imbalance between cell wall production and degradation develops and causing the bacterial cells to die rapidly. In addition, the enzymes that hydrolyze the peptidoglycan cross-links continue to perform. This weakens the cell wall of the bacterium further, which increases the osmotic pressure and eventually causing cell death (cytolysis). At last, the build-up of peptidoglycan precursors induces the activation of bacterial cell wall hydrolases and autolysins, and further digests the cell wall's peptidoglycans. The small size penicillin/penicillin derivatives via penetrating the entire depth of the cell wall to increase their potency.

Fig.1 Mechanism of penicillin action. PGN is composed of polysaccharide chains made of GlcNAc and MurNAc units (shown in different shades of blue) which in turn have small peptides attached to them. The transpeptidase enzyme (PBP) (in brown) catalyzes the formation of cross-linkages between these peptides, by specifically binding the last two D-alanine residues of one peptide (red circles). Penicillin mimics the structure of these residues and inactivates the PBP by forming an irreversible covalent bond to the catalytic serine residue of the enzyme. (Lobanovska, 2017)

Penicillin Derivatives-based AACs

At present, AACs are under active development and penicillin derivatives antibiotic can be used as payloads for customized AAC generation. In detail, the specific monoclonal antibody can deliver penicillin derivatives exclusively to the infection site. Upon anti-bacteria mAb binding to antigen, AAC is internalized via receptor-mediated endocytosis and the penicillin derivatives payload is released to achieve sterilization.

Fig.2 Antibody-antibiotic conjugates (AACs) to fight infectious disease. The site-specific conjugation of molecules to monoclonal antibodies has a wide range of applications. Site-specific conjugation decreases conjugate heterogeneity and improves stability and function. (Mariathasan, 2017)

Creative Biolabs is dedicated to helping clients develop penicillin derivatives-linker complexes in a timely and cost-effective manner. Our customized services will contribute greatly to the success of your projects. Other various services regarding AAC development are also are available. Please feel free to contact us for more information and a detailed quote.

References:

1. Lobanovska, M.; Pilla, G. (2017). “Focus: Drug Development: Penicillin’s Discovery and Antibiotic Resistance: Lessons for the Future?”. The Yale journal of biology and medicine, 90(1), 135.
2. Mariathasan, S.; Tan, M. W. (2017). “Antibody-antibiotic conjugates: a novel therapeutic platform against bacterial infections”. Trends in Molecular Medicine, 23(2), 135.