Penicillins are often more effective against gram-positive bacteria than gram- negative bacteria primarily due to differences in bacterial cell wall structure and permeability. Gram-positive bacteria have a thick peptidoglycan layer that is directly accessible to penicillins. Penicillin molecules can easily penetrate this thick layer because gram-positive bacteria lack an outer membrane, allowing penicillin to inhibit the enzymes responsible for cross- linking peptidoglycan strands, which weakens the cell wall and causes bacterial cell death. In contrast, gram-negative bacteria have a more complex cell envelope with an outer membrane that acts as a barrier, blocking many molecules including penicillin. Penicillins must enter gram-negative cells through porin channels in the outer membrane, which restricts the rate and amount of antibiotic penetration. Additionally, gram-negative bacteria have a thinner peptidoglycan layer located beneath the outer membrane, making them less susceptible. Some larger penicillin molecules enter slowly or cannot pass efficiently through porins, reducing penicillin's effectiveness against gram- negative species. Therefore, the greater accessibility of the target (peptidoglycan layer) and less restrictive cell envelope in gram-positive bacteria make penicillins more effective against them compared to gram- negative bacteria.