Modifying the structure of existing antibiotics to increase their efficacy against drug-resistant bacterial strains can be achieved through several approaches. These approaches involve altering the chemical structure of the antibiotic to improve its pharmacokinetic properties, reduce bacterial resistance mechanisms, and enhance its activity against the target. Here, we will discuss three main strategies: 1 derivatization, 2 conjugation, and 3 hybridization.1 Derivatization:Derivatization involves making small chemical modifications to the existing antibiotic structure to improve its properties. This can be achieved through various chemical reactions, such as esterification, acylation, or halogenation. For example, the semi-synthetic penicillin antibiotic amoxicillin is derived from the natural penicillin molecule by adding an amino group to the side chain. This modification increases the antibiotic's spectrum of activity and makes it more resistant to bacterial enzymes beta-lactamases that degrade the beta-lactam ring.Synthesis of amoxicillin from 6-aminopenicillanic acid 6-APA :6-APA is reacted with a suitable acylating agent, such as D- - --phenylglycine, in the presence of a coupling agent like dicyclohexylcarbodiimide DCC or 1-ethyl-3- 3-dimethylaminopropyl carbodiimide EDC . This reaction forms an amide bond between the carboxylic acid group of 6-APA and the amine group of D- - --phenylglycine, resulting in the formation of amoxicillin.2 Conjugation:Conjugation involves attaching a functional group or another molecule to the existing antibiotic structure to improve its properties. This can be achieved through various chemical reactions, such as amide bond formation, click chemistry, or disulfide bond formation. For example, conjugating an antibiotic with a cell-penetrating peptide CPP can enhance its cellular uptake and intracellular activity against intracellular pathogens.Synthesis of antibiotic-CPP conjugate:The antibiotic and CPP can be conjugated using a suitable linker, such as a polyethylene glycol PEG chain. The carboxylic acid group of the antibiotic can be activated using a coupling agent like EDC or DCC, and then reacted with the amine group of the CPP in the presence of a suitable base, such as N,N-diisopropylethylamine DIPEA , to form an amide bond.3 Hybridization:Hybridization involves combining two or more existing antibiotics or pharmacophores into a single molecule to improve their properties and overcome bacterial resistance mechanisms. This can be achieved through various chemical reactions, such as amide bond formation, click chemistry, or disulfide bond formation. For example, a hybrid molecule containing a beta-lactam antibiotic and a quinolone antibiotic can be designed to target both the bacterial cell wall and DNA synthesis, reducing the likelihood of resistance development.Synthesis of beta-lactam-quinolone hybrid:The carboxylic acid group of the beta-lactam antibiotic can be activated using a coupling agent like EDC or DCC, and then reacted with the amine group of the quinolone antibiotic in the presence of a suitable base, such as DIPEA, to form an amide bond. Alternatively, a suitable linker, such as a PEG chain or a triazole ring formed via click chemistry , can be used to connect the two antibiotic moieties.In conclusion, modifying the structure of existing antibiotics through derivatization, conjugation, or hybridization can increase their efficacy against drug-resistant bacterial strains. These strategies involve altering the chemical structure of the antibiotic to improve its pharmacokinetic properties, reduce bacterial resistance mechanisms, and enhance its activity against the target.