Bacteria resistant to penicillin and other β-lactam antibiotics avoid being killed by these drugs by producing the enzyme β-lactamase. β-lactamase acts by cleaving the carbon-nitrogen bond in the antibiotic’s β-lactam ring.

Both gram-positive and gram-negative bacteria of various species produce β-lactamase. Depending on species, bacteria may be induced to produce it (called an inducible enzyme) when they detect the presence of an antibiotic, then excrete the enzyme into the surroundings. In other cases, the enzyme is called a constitutive enzyme, which is present in the cell at all times but becomes active only when needed. Constitutive β-lactamase works at or near the cell membrane and does not leave the cell.

In Staphylococcus, a protein that is a normal constituent of the cell membrane (called an integral protein) makes up part of the bacterium’s control of inducible β-lactamase production. This integral protein is called the signaler for the presence of penicillin. When the signaler becomes activated by binding to penicillin, it turns on gene expression of β-lactamase production. Gene expression is the process of turning the information carried in genes into a functioning protein. A second protein, called a repressor, normally blocks the gene expression. At the same time that the signaler-penicillin reaction notifies the cell that penicillin is in the vicinity, the repressor also becomes inactivated. The signaler and the repressor work in tandem as a control mechanism, for turning on β-lactamase production, when the cell needs protection from penicillin, and turning it off, when the danger has passed.

All β-lactamases have the same goal of deactivating a β-lactam antibiotic before the substance can kill the cell. The enzymes differ slightly among species in the base sequences in their genes and in the antibiotics against which they work best. Microbiologists have categorized β-lactamases according to the main antibiotics they inactivate. More recent studies of the genes that control β-lactamase and of the enzyme’s structure have provided more detail on the enzyme at a molecular level. The table below describes β-lactamase categories based on enzyme structure and, thus, activity against specific antibiotics.

The table indicates that plasmids play an important role in antibiotic resistance. These small circular pieces of deoxyribonucleic acid (DNA), in fact, have been linked with various types of antibiotic resistance, in addition to β-lactam resistance. Different strains and species can transfer resistance among them by sharing plasmids.

Biochemists have invented countermeasures to bacteria’s use of β-lactamase. Compounds called β-lactamase inhibitors inactivate β-lactamase and, thus, allow the antibiotic to regain activity. Physicians prescribe β-lactamase inhibitors to be given with β-lactam antibiotics to boost the antibiotics’ effectiveness.

Bacteria have developed resistance to third- and even fourth-generation penicillins; therefore, microbiologists now seek entirely different antibiotics, rather than planning for additional generations of the drug. The Staphylococcus known as methicillin-resistant S. aureus (MRSA) has developed resistance against all penicillin generations, so physicians must now treat MRSA infections with the antibiotic vancomycin, which is still effective against this bacterium. Hints of MRSA resistance to vancomycin are beginning to appear in microbiology. If the microorganism devel ops strong resistance to this antibiotic, doctors will have few or no weapons against MRSA infections.