How do bacteria resist antibiotics?

The extensive use of antibiotics in health care has resulted in a rise in pathogenic bacteria and other microorganisms that are resistant to antibiotics. In the year 2021, about 1.2 million deaths worldwide were attributed to antimicrobial resistance to existing antibiotics. Surveys in Indian hospitals show that infections with drug-resistant bacteria have a 13% mortality rate. Therefore, the search for new antibiotics is a high-priority area of research.

Antibiotics literally means against life. But antibiotics are specifically used for killing bacteria and other microorganisms or for inhibiting their growth, without harming human cells.

Unique cell walls

A distinguishing feature of bacterial cells is the presence of a cell wall that forms a sheath over the cell membrane. Our cells do not have cell walls. Bacterial cell walls are primarily made of a unique substance called peptidoglycan, which is a mesh-like structure mostly made of two components.

Glycans are long chains of alternating sugar molecules called NAG (N-acetylglucosamine) and NAM (N-acetylmuramic acid). The NAM-NAG unit, linked into long chains, is unique to bacteria. This uniqueness makes it an important target for antibiotic development. Our immune system too looks for this signature to attack invading bacteria.

The ‘peptido’ portion of peptidoglycans are peptides (short amino acid chains) that link NAM sugars on adjacent glycan strands. The crosslinks form a strong, interconnected mesh. The first antibiotic to be discovered, penicillin, works by interfering with this crosslinking step. The result is a weakened cell wall that can no longer securely hold the cytoplasm, and the bacterial cell bursts open and dies.

Evolution of resistance

How did bacteria evolve resistance to penicillin? They came up with new enzymes, (e.g., penicillinase) which chop up penicillin molecules. Or, they evade antibiotic action by modifying the targets of penicillin.

Bacterial infection requires rapid division of bacterial cells, for which cell wall synthesis is needed. To understand bacterial cell division, let us use the children’s game LEGO as a simplified analogy. Picture a square cell that is six inches on each side, with walls made of LEGO tiles. To make this cell divide, you would add tiles to two opposite sides until it becomes a rectangle that is twelve inches by six inches. Then you would extend the walls along the middle, creating two six-inch square daughter cells. 

Real bacterial cells must synthesise their own wall material. And just as some links in a LEGO wall must be uncoupled to enable the addition of fresh tiles, bacteria selectively break and reform bonds within the existing wall to allow for growth and division. Before new cell wall components can be added, molecular scissors are used: enzymes called endopeptidases uncouple the peptide crosslinks, and lytic transglycosylases (LTs) cleave the backbone sugar chains. Both of these have to work in harmony, and the bacterial machinery that regulates this process is very complex — new components continue to be discovered.

The group of Dr. Manjula Reddy at the Centre for Cellular and Molecular Biology, Hyderabad, works on mechanisms that enable bacteria to precisely control cell division. In a study published last year in PLOS Genetics, they have shown that bacteria are clever and can make up for the loss of the crosslink-cutting scissors by making an excess of the chain-cutting LT scissors. New findings in this field facilitate a better understanding of how bacteria survive against all odds. Such insights will pave the way for new strategies to fight bacterial infections.

(The article was written in collaboration with Sushil Chandani, who works in molecular modelling. sushilchandani@gmail.com)