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Antimicrobial resistance (AMR) is likely to be one of the greatest challenges faced by humanity and if nothing changes it is projected to kill one person every 5 seconds by 2050. Despite this, there are few new therapeutic options in development and so there is a need for new solutions to be identified. One new strategy is the reverse antibiotic approach originally published by Akamatsu and co-workers. Here treatment with the first antibiotic leads to resistance so a new antibiotic is needed. Resistance to the second antibiotic can only be achieved by a back-mutation thus re-sensitising the bacteria to the first antibiotic. The bacteria will be trapped in an ‘evolutionary loop’ where it will always be sensitive to either the first or second antibiotic. Work outlined in this thesis will look to investigate and develop one of the key series of antibiotics in the reverse antibiotic approach, the Nybomycin family of natural products. A new robust and scalable synthetic route that facilitated the synthesis of the best literature compound DNM-2, as well as novel analogues to probe the SAR, is reported. The whole cell inhibition of these compounds is reported as well as selected analogue’s enzymatic inhibition of the key biological targets. The ability of the series to inhibit Gram-negative bacteria was also explored and led to the discovery that the series is a substrate for efflux via the AcrAB/TolC efflux channel. However, the compounds are active in E. coli if TolC or AcrB is removed. After initial profiling, aqueous solubility was found to be the major hurdle in the development of the series. This was addressed using medicinal chemistry techniques as well as computational chemistry to aid in the design of novel analogues. This led to the discovery of 6DNM-2-L1A, the most potent and soluble analogue tested to date. Open Access