Entry into bacteria<unk>  can easily enter bacterial cell in case of Gram-positive species. This is because Gram-positive bacteria do not have an outer cell membrane and are simply enclosed in a thick cell wall.<unk>  molecules are small enough to pass through the spaces of glycoproteins in the cell wall. For this reason Gram-positive bacteria are very susceptible to<unk>  (as first evidenced by the discovery of<unk>  in 1928).<unk> , or any other molecule, enters Gram-negative bacteria in a different manner. The bacteria have thinner cell walls but the external surface is coated with an additional cell membrane, called the outer membrane. The outer membrane is a lipid layer (lipopolysaccharide chain) that blocks passage of water-soluble (hydrophilic) molecules like<unk> . It thus acts as the first line of defence against any toxic substance, which is the reason for relative resistance to antibiotics compared to Gram-positive species But<unk>  can still enter Gram-negative species by diffusing through aqueous channels called porins (outer membrane proteins), which are dispersed among the fatty molecules and can transport nutrients and antibiotics into the bacteria. Porins are large enough to allow diffusion of most<unk> s, but the rate of diffusion through them is determined by the specific size of the drug molecules. For instance,<unk>  G is large and enters through porins slowly; while smaller ampicillin and amoxicillin diffuse much faster. In contrast, large vancomycin can not pass through porins and is thus ineffective for Gram-negative bacteria. The size and number of porins are different in different bacteria. As a result of the two factors—size of<unk>  and porin—Gram-negative bacteria can be unsusceptible or have varying degree of susceptibility to specific<unk> . Mechanism of action 600px<unk>  and other β-lactam antibiotics act by inhibiting<unk> -binding proteins, which normally catalyze cross-linking of bacterial cell walls. The chemical structure of<unk>  is triggered with a very precise, pH-dependent directed mechanism, affected by a unique spatial assembly of molecular components, which can activate by protonation. It can travel through bodily fluids, targeting and inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria, meanwhile avoiding the surrounding non-targets.<unk>  can protect itself from spontaneous hydrolysis in the body in its anionic form while storing its potential as a strong acylating agent, activated only upon approach to the target transpeptidase enzyme and protonated in the active centre. This targeted protonation neutralizes the carboxylic acid moiety, which is weakening of the β-lactam ring N–C(=O) bond, resulting in a self-activation. Specific structural requirements are equated to constructing the perfect mousetrap for catching targeted prey.<unk>  kills bacteria by inhibiting the completion of the synthesis of peptidoglycans, the structural component of bacterial cell wall. It specifically inhibits the activity of enzymes that are needed for the cross-linking of peptidoglycans during the final step in cell wall biosynthesis. It does this by binding to<unk>  binding proteins with the β-lactam ring, a structure found on<unk>  molecules. This causes the cell wall to weaken due to fewer cross-links and means water uncontrollably flows into the cell because it cannot maintain the correct osmotic gradient. This results in cell lysis and death. Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide. During the last stages of peptidoglycan biosynthesis, uridine diphosphate-N-acetylmuramic acid pentapeptide (UDP-MurNAc) is formed in which the fourth and fifth amino acids are both D-alanyl-D-alanine. The transfer of D-alanine is done (catalysed) by the enzyme DD-transpeptidase<unk> -binding proteins are such type). The structural integrity of bacterial cell wall depends on the cross linking of UDP-MurNAc and N-acetyl glucosamine.<unk>  and other β-lactam antibiotics act as an analogue of D-alanine-D-alanine (the dipeptide) in UDP-MurNAc owing to conformational similarities. The DD-transpeptidase then binds the four-membered β-lactam ring of<unk>  instead of UDP-MurNAc. As a consequence, DD-transpeptidase is inactivated, the formation of cross-links between UDP-MurNAc and N-acetyl glucosamine is blocked so that an imbalance between cell wall production and degradation develops, causing the cell to rapidly die. The enzymes that hydrolyze the peptidoglycan cross-links continue to function, even while those that form such cross-links do not. This weakens the cell wall of the bacterium, and osmotic pressure becomes increasingly uncompensated—eventually causing cell death (cytolysis). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the cell wall's peptidoglycans. The small size of the<unk> s increases their potency, by allowing them to penetrate the entire depth of the cell wall. This is in contrast to the glycopeptide antibiotics vancomycin and teicoplanin, which are both much larger than the<unk> s. Gram-positive bacteria are called protoplasts when they lose their cell walls. Gram-negative bacteria do not lose their cell walls completely and are called spheroplasts after treatment with<unk> .<unk>  shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing their disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms.<unk> s, like other β-lactam antibiotics, block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts of bryophytes. In contrast, they have no effect on the plastids of the highly developed vascular plants. This supports the endosymbiotic theory of the evolution of plastid division in land plants. Some bacteria produce enzymes that break down the β-lactam ring, called β-lactamases, which make the bacteria resistant to<unk> . Therefore, some<unk> s are modified or given with other drugs for use against antibiotic-resistant bacteria or in immunocompromised patients. The use of clavulanic acid or tazobactam, β-lactamase inhibitors, alongside<unk>  gives<unk>  activity against β-lactamase-producing bacteria. β-Lactamase inhibitors irreversibly bind to β-lactamase preventing it from breaking down the beta-lactam rings on the antibiotic molecule. Alternatively, flucloxacillin is a modified<unk>  that has activity against β-lactamase-producing bacteria due to an acyl side chain that protects the beta-lactam ring from β-lactamase. Pharmacokinetics<unk>  has low protein binding in plasma. The bioavailability of<unk>  depends on the type:<unk>  G has low bioavailability, below 30%, whereas<unk>  V has higher bioavailability, between 60 and 70%.<unk>  has a short half-life and is excreted via the kidneys. This means it must be dosed at least four times a day to maintain adequate levels of<unk>  in the blood. Early manuals on the use of<unk> , therefore, recommended injections of<unk>  as frequently as every three hours, and dosing<unk>  has been described as being similar to trying to fill a bath with the plug out. This is no longer required since much larger doses of<unk>  are cheaply and easily available; however, some authorities recommend the use of continuous<unk>  infusions for this reason.
Penicillin
Carbenicillin
Extended-spectrum penicillin
Tetracycline
Phenoxymethylpenicillin
Benzylpenicillin
Piperacillin
Methicillin