Why are gram-positive bacteria more susceptible to antibiotics?

From the Guidelines

Gram-positive bacteria are more susceptible to antibiotics due to their simpler cell wall structure, which allows antibiotics to penetrate more easily and reach their targets. The cell wall of gram-positive bacteria consists primarily of a thick layer of peptidoglycan, as described in the study 1, without the additional outer membrane found in gram-negative bacteria. This structural difference is a key factor in the susceptibility of gram-positive bacteria to antibiotics. Some key points to consider when treating gram-positive infections include:

• The lack of an outer membrane in gram-positive bacteria reduces the barrier to antibiotic penetration, making them more susceptible to antibiotics such as penicillins, cephalosporins, vancomycin, and macrolides.
• The presence of penicillin-binding proteins (PBPs) in gram-positive bacteria, as mentioned in the study 1, provides a target for beta-lactam antibiotics, which can inhibit cell wall synthesis and ultimately lead to bacterial cell death.
• The simpler cell wall structure of gram-positive bacteria also reduces the risk of antibiotic resistance due to efflux pumps, which are more commonly found in gram-negative bacteria. Overall, the susceptibility of gram-positive bacteria to antibiotics is a critical consideration in clinical practice, and understanding the structural differences between gram-positive and gram-negative bacteria is essential for selecting effective antibiotic therapy, as highlighted in the study 1.

From the FDA Drug Label

Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive bacteria in vitro. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely

Gram-positive bacteria are more susceptible to antibiotics because of their unique cell wall structure and membrane composition. The mechanism of action of antibiotics such as daptomycin and linezolid, which target the bacterial cell membrane and protein synthesis, respectively, makes them more effective against gram-positive bacteria.

• Daptomycin binds to the bacterial cell membrane, causing rapid depolarization and inhibition of DNA, RNA, and protein synthesis, leading to bacterial cell death.
• Linezolid binds to the 23S ribosomal RNA of the 50S subunit, preventing the formation of a functional 70S initiation complex and inhibiting protein synthesis. The exact reason for the increased susceptibility of gram-positive bacteria to antibiotics is not fully understood, but it is thought to be related to the thickness and composition of the peptidoglycan layer in the cell wall, as well as the presence of teichoic acids. Key points:
• Gram-positive bacteria have a thicker peptidoglycan layer than gram-negative bacteria.
• The peptidoglycan layer in gram-positive bacteria is more accessible to antibiotics.
• Teichoic acids in gram-positive bacteria may play a role in the uptake and retention of antibiotics. Overall, the combination of the unique cell wall structure and membrane composition of gram-positive bacteria, along with the mechanism of action of antibiotics such as daptomycin and linezolid, makes them more susceptible to these antibiotics 2, 3.

From the Research

Susceptibility of Gram-Positive Bacteria to Antibiotics

• Gram-positive bacteria are generally more susceptible to antibiotics due to their cell wall structure, which is composed of a thick layer of peptidoglycan [ 4 ].
• The peptidoglycan layer in Gram-positive bacteria is tens of nanometres thick and provides mechanical strength to the cell [ 4 ].
• However, this thick layer also makes it more accessible to antibiotics that target peptidoglycan synthesis, such as beta-lactam antibiotics [ 5 ].

Mechanisms of Resistance

• Despite their susceptibility, Gram-positive bacteria can develop resistance to antibiotics through various mechanisms, including genetic mutations and acquired genomes [ 6 ].
• Methicillin-resistant Staphylococcus aureus (MRSA) is a notable example of a Gram-positive bacterium that has developed resistance to beta-lactam antibiotics [ 5 ].
• Vancomycin-resistant Enterococcus faecium is another example of a Gram-positive bacterium that has developed resistance to antibiotics [ 6 ].

Treatment Options

• Beta-lactam antibiotics, such as cloxacillin and cefazolin, are effective against methicillin-susceptible Staphylococcus aureus (MSSA) [ 7 ].
• Cefazolin has been shown to be as effective as antistaphylococcal penicillins in the treatment of MSSA bacteremia [ 8 ].
• However, the rise of multidrug-resistant Gram-positive bacteria requires continuous efforts to develop new treatments and strategies to combat antibiotic resistance [ 6 ].