Study offers a fascinating look into antibiotics development

Antibiotic resistance is a significant and increasing problem in healthcare, as more and more strains of bacteria are developing resistance to some of our strongest, last-resort antibiotics. Among these are β-lactams, which are a large group of antibiotics including penicillin derivatives, cephalosporins, monobactams, and carbapenems. These drugs all contain a β-lactam ring, which disrupts the biosynthesis of the bacterial cell wall. Unfortunately, resistance factors can include β-lactamase enzymes that break down and inactivate the key component of these medications.

To get around this, one method researchers employ is to add a separate compound that targets the antibiotic-degrading enzymes, but this is less efficient than making the antibiotic molecule itself resistant to degradation. One way to accomplish this is to leverage steric (space filling) interactions between inert "add-on" groups that essentially make the antibiotic the wrong shape to fit in the degrading enzyme, but still leave it effective in killing the bacteria.

In this study, researchers tested several different compounds based on a β-lactam ring altered by 1, 3-dipolar cycloaddition (addition of a ring-shaped subunit at each end), which in theory should retain some antibacterial activity while avoiding degradation by antibiotic-resistant enzymes. These compounds were tested against an ex vivo model with bacteria cultured on harvested dentin, an in vivo model on mouse caries, and a mammalian toxic/mutagenic assay.

Of the 15 compounds tested, compound #3 showed an exciting ability to kill E. faecalis, a bacteria commonly discovered in failed root canals, as well as broad-spectrum efficacy against a variety of gram-positive and gram-negative bacteria. However, just because a compound is antibacterial doesn't mean it's safe for use – methanol is strongly bactericidal, but you wouldn't want to swish with it instead of chlorhexidine! Thus, preliminary safety tests must determine whether the compound is hemocompatible (doesn't interact with the blood supply) and does not harm or mutate mammalian cells. Compound #3, in this case, passed all three tests, and is recommended for further investigation, which may ultimately lead to its development as a new antibiotic. Very few compounds make it all the way through extensive testing and FDA approval, however.

As one can tell from the lengthy and complicated process described above, prevention of antibiotic resistance is a much more effective strategy to combat resistant bacteria than inventing new antibiotics from scratch.

Source:


Meiyazhagan G, Raju R, Winfred SB, Mannivanan B, Bhoopalan H, Shankar V, et al. (2015) Bioactivity Studies of β-Lactam Derived Polycyclic Fused Pyrroli-Dine/Pyrrolizidine Derivatives in Dentistry: In Vitro, In Vivo and In Silico Studies. PLoS ONE 10(7): e0131433. https://doi.org/10.1371/journal.pone.0131433

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