Antibiotic resistance is a major public health threat, with multidrug-resistant organisms now present in both hospital and community settings. Bacteria respond to antibiotics through genetic adaptations, including mutations, acquisition of genetic material, and alterations in gene expression, leading to resistance. Understanding the biochemical and genetic basis of resistance is crucial for developing strategies to combat resistance and create new therapies. This article details the major mechanisms of antibiotic resistance encountered in clinical practice, focusing on bacterial pathogens. Bacteria use two main genetic strategies to adapt to antibiotics: mutations in genes involved in the drug's mechanism of action and horizontal gene transfer (HGT). Mutational resistance involves changes that alter the antibiotic's target, reduce drug uptake, activate efflux mechanisms, or modify metabolic pathways. HGT allows bacteria to acquire resistance genes from other organisms, often through plasmids, transposons, or integrons. The article explores various resistance mechanisms, including modifications of the antibiotic molecule, prevention of antibiotic penetration, and changes in target sites. Enzymes like aminoglycoside modifying enzymes (AMEs) inactivate antibiotics, while β-lactamases destroy β-lactam antibiotics. Resistance to β-lactams in gram-negative bacteria is often due to β-lactamases, while gram-positive bacteria use modifications of their target sites. Other mechanisms include decreased antibiotic penetration through altered porins or efflux pumps, which actively expel antibiotics from the cell. Efflux pumps are categorized into families such as MFS, RND, ABC, and MATE, with RND pumps being particularly important in gram-negative bacteria. Additionally, bacteria can modify their target sites to reduce antibiotic affinity, such as changes in DNA gyrase or topoisomerase IV for fluoroquinolone resistance. The article highlights the importance of understanding these mechanisms to develop effective strategies against antibiotic resistance. It also discusses the role of integrons in accumulating resistance genes and the global spread of resistance determinants like NDM-1. The complexity of these mechanisms underscores the need for continued research and innovative approaches to combat the growing threat of antibiotic resistance.Antibiotic resistance is a major public health threat, with multidrug-resistant organisms now present in both hospital and community settings. Bacteria respond to antibiotics through genetic adaptations, including mutations, acquisition of genetic material, and alterations in gene expression, leading to resistance. Understanding the biochemical and genetic basis of resistance is crucial for developing strategies to combat resistance and create new therapies. This article details the major mechanisms of antibiotic resistance encountered in clinical practice, focusing on bacterial pathogens. Bacteria use two main genetic strategies to adapt to antibiotics: mutations in genes involved in the drug's mechanism of action and horizontal gene transfer (HGT). Mutational resistance involves changes that alter the antibiotic's target, reduce drug uptake, activate efflux mechanisms, or modify metabolic pathways. HGT allows bacteria to acquire resistance genes from other organisms, often through plasmids, transposons, or integrons. The article explores various resistance mechanisms, including modifications of the antibiotic molecule, prevention of antibiotic penetration, and changes in target sites. Enzymes like aminoglycoside modifying enzymes (AMEs) inactivate antibiotics, while β-lactamases destroy β-lactam antibiotics. Resistance to β-lactams in gram-negative bacteria is often due to β-lactamases, while gram-positive bacteria use modifications of their target sites. Other mechanisms include decreased antibiotic penetration through altered porins or efflux pumps, which actively expel antibiotics from the cell. Efflux pumps are categorized into families such as MFS, RND, ABC, and MATE, with RND pumps being particularly important in gram-negative bacteria. Additionally, bacteria can modify their target sites to reduce antibiotic affinity, such as changes in DNA gyrase or topoisomerase IV for fluoroquinolone resistance. The article highlights the importance of understanding these mechanisms to develop effective strategies against antibiotic resistance. It also discusses the role of integrons in accumulating resistance genes and the global spread of resistance determinants like NDM-1. The complexity of these mechanisms underscores the need for continued research and innovative approaches to combat the growing threat of antibiotic resistance.