Following the rules to foil Gram-negative infections

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Science Translational Medicine  03 Jun 2020:
Vol. 12, Issue 546, eabc8938
DOI: 10.1126/scitranslmed.abc8938


Molecular design principles increase accumulation of an antibiotic in multidrug resistant Gram-negative bacteria.

A major obstacle in developing new antibiotics for Gram-negative infections is the difficulty of concentrating small molecules within Gram-negative (GN) bacteria. This difficulty stems from both the presence of densely packed lipopolysaccharides (LPS) and nonspecific efflux pumps. Ribocil C targets the flavin mononucleotide (FMN) riboswitch and essentially starves bacteria of riboflavin, leading to cell death. Notably, there are no known riboswitches in mammalian systems. This compound has demonstrated activity against Gram-positive bacteria such as Staphylococcus aureus and Escherichia. coli strains with permeability defects but is ineffective against most GN bacteria. Motika et al. set out to modify Ribocil C in ways that would favor its accumulation within GN bacteria.

In a series of elegant experiments spanning compound synthesis to testing in mice, the authors applied previous findings wherein small molecules that contain few rotatable bonds, include an ionizable nitrogen (ideally a primary amine), and have flat or linear structures (as opposed to spherical structures) are more likely to accumulate in GN bacteria. Ribocil C already meets two of the three criteria by being relatively planar and having a low number of rotatable bonds. The researchers added primary amine groups to generate new classes of Ribocil C derivatives and comprehensively characterized a subset of these compounds. A particularly promising derivative, Riobcil C-PA, showed minimal toxicity in mammalian cell culture. Treatment with Ribocil C-PA increased survival in septic mice injected with a multidrug resistant strain of E. coli compared to unmodified Ribocil C. Additionally, treatment with Riboc22il C-PA decreased bacterial counts in an acute E. coli pneumonia model.

As demonstrated by this study, researchers are now able to take promising lead compounds and rationally modify them to increase accumulation in GN bacteria, opening up new antimicrobial strategies. One important limitation is that the authors were also able to generate several mutant stains of E. coli with resistance to Riobcil C-PA; as expected, these strains all had mutations in the FMN riboswitch. Although following rational design rules to produce new antibiotics is a promising approach, GN bacteria seem poised to evolve new drug-resistance mechanisms in response.

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