This review explores the mechanisms of antibiotic resistance in Klebsiella pneumoniae (K. pneumoniae) and highlights the need for new therapeutic strategies. K. pneumoniae is a Gram-negative bacteria that causes various infections, particularly in immunocompromised individuals. The emergence of multidrug-resistant (MDR) strains has become a major global health concern, with resistance mechanisms including the production of extended-spectrum beta-lactamases (ESBLs), carbapenemases, and porin loss. These mechanisms enable the bacteria to resist a wide range of antibiotics, including beta-lactams, fluoroquinolones, and aminoglycosides. Additionally, biofilm formation contributes to antibiotic resistance by protecting the bacteria from antimicrobial agents. The review discusses various resistance mechanisms, such as intrinsic resistance, acquired resistance through horizontal gene transfer, and the role of efflux pumps. It also highlights the challenges in treating MDR K. pneumoniae infections, as conventional antibiotics are often ineffective. The study emphasizes the importance of identifying new pharmacological targets for drug development, such as enzymes involved in fatty acid biosynthesis, lipid A synthesis, and cell wall formation. Potential targets include FabB, FabI, FabH, LpxA, LpxB, LpxC, LpxD, MurG, and MurF. These targets are promising for developing new antibiotics that can overcome resistance mechanisms in K. pneumoniae. The review also discusses the role of bacterial two-component systems, such as EvgS/EvgA and QseC, in antibiotic resistance and virulence. The study concludes that understanding the molecular mechanisms of antibiotic resistance in K. pneumoniae is crucial for developing new therapeutic strategies to combat this global health threat. The identification of novel drug targets and the development of new antibiotics are essential to address the growing problem of antibiotic resistance in K. pneumoniae infections.This review explores the mechanisms of antibiotic resistance in Klebsiella pneumoniae (K. pneumoniae) and highlights the need for new therapeutic strategies. K. pneumoniae is a Gram-negative bacteria that causes various infections, particularly in immunocompromised individuals. The emergence of multidrug-resistant (MDR) strains has become a major global health concern, with resistance mechanisms including the production of extended-spectrum beta-lactamases (ESBLs), carbapenemases, and porin loss. These mechanisms enable the bacteria to resist a wide range of antibiotics, including beta-lactams, fluoroquinolones, and aminoglycosides. Additionally, biofilm formation contributes to antibiotic resistance by protecting the bacteria from antimicrobial agents. The review discusses various resistance mechanisms, such as intrinsic resistance, acquired resistance through horizontal gene transfer, and the role of efflux pumps. It also highlights the challenges in treating MDR K. pneumoniae infections, as conventional antibiotics are often ineffective. The study emphasizes the importance of identifying new pharmacological targets for drug development, such as enzymes involved in fatty acid biosynthesis, lipid A synthesis, and cell wall formation. Potential targets include FabB, FabI, FabH, LpxA, LpxB, LpxC, LpxD, MurG, and MurF. These targets are promising for developing new antibiotics that can overcome resistance mechanisms in K. pneumoniae. The review also discusses the role of bacterial two-component systems, such as EvgS/EvgA and QseC, in antibiotic resistance and virulence. The study concludes that understanding the molecular mechanisms of antibiotic resistance in K. pneumoniae is crucial for developing new therapeutic strategies to combat this global health threat. The identification of novel drug targets and the development of new antibiotics are essential to address the growing problem of antibiotic resistance in K. pneumoniae infections.