Antibiotic resistance has become increasingly concerning over the past few decades. One reason for this is the dearth of new classes of antibiotics, as only two in the last half century have made it successfully to the market, both of which are only active against Gram-positive bacteria. Disturbingly, bacteria developed resistance to both classes within just a few years of clinical use. This signals that a new approach to combat drug resistant bacteria must be taken. An alternative approach to developing new antibiotics is to use a non-toxic small molecule as an adjuvant to lower the dosage of a conventional antibiotic needed to overcome Gram-negative bacterial infections. Colistin, produced in the 1950’s, is known as a last resort antibiotic for Gram-negative bacterial infections that are resistant to all other classes because of its effectiveness and its resulting kidney toxicity, as 1 in 4 patients develop kidney damage after a full treatment regimen. Troublingly, plasmid-borne gene mobile colistin resistance-1 (mcr-1) has been observed that encodes resistance to colistin through modification of the cell’s lipopolysaccharide (LPS) surface of the outer membrane. This small molecule approach could prove beneficial for the receiving patient as smaller amounts of colistin are needed to rid the patient of bacteria while overcoming resistance. These small molecules have shown the ability to lower the minimum inhibitory concentration (MIC) of colistin against various Gram-negative pathogens. In a strain of Acinetobacter baumannii, one compound caused an 8,000-fold reduction in the MIC of colistin, and also showed similar activity in multiple strains of A. baumannii along with a Klebsiella pneumoniae strain.

Utilizing small molecule adjuvants to increase colistin efficacy against Gram-negative bacteria

255th National Meeting (2018)

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