The recent advances in the application of machine learning to drug discovery have made it a 'hot topic' for research, with hundreds of academic groups and companies integrating machine learning into their drug discovery projects. Nevertheless, there remains great uncertainty regarding the most appropriate ways to evaluate the relative performance of these powerful methods against more traditional cheminformatics approaches, and many pitfalls remain for the unwary. In 2020, researchers at MIT (Stokes et al., Cell 180(4), 688-702, 2020) reported the discovery of a new compound with antibacterial activity, halicin, through the use of a neural network machine learning method. A robust ability to identify new active chemotypes through computational methods would be very useful. In this study, we have used the Stokes et al. dataset to compare the performance of this method to two other approaches, Mapping of Activity Through Dichotomic Scores (MADS) by Todeschini et al. (J Chemom 32(4):e2994, 2018) and Random Matrix Theory (RMT) by Lee et al. (Proc Natl Acad Sci 116(9):3373-3378, 2019). Our results demonstrate that all three methods are capable of predicting halicin as an active antibacterial compound, but that this result is dependent on the dataset composition, pre-processing and the molecular fingerprint used. We have further assessed overall performance as determined by several performance metrics. We also investigated the scaffold hopping potential of the methods by modifying the dataset by removal of the β-lactam and fluoroquinolone chemotypes. MADS and RMT are able to identify actives in the test set that contained these substructures. This ability arises because of high scoring fragments of the withheld chemotypes that are in common with other active antibiotic classes. Interestingly, MADS is relatively better compared to the other two methods based on general predictive performance.