Antimicrobial resistance (AMR) is one of the serious global health challenges of our time. There is now an urgent need to develop novel therapeutic agents that can overcome AMR, preferably through alternative mechanistic pathways from conventional treatments. The antibacterial activity of metal complexes (metal = Cu(II), Mn(II), and Ag(I)) incorporating 1,10-phenanthroline (phen) and various dianionic dicarboxylate ligands, along with their simple metal salt and dicarboxylic acid precursors, against common AMR pathogens were investigated. Overall, the highest level of antibacterial activity was evident in compounds that incorporate the phen ligand compared to the activities of their simple salt and dicarboxylic acid precursors. The chelates incorporating both phen and the dianion of 3,6,9-trioxaundecanedioic acid (tdda) were the most effective, and the activity varied depending on the metal centre. Whole-genome sequencing (WGS) was carried out on the reference Pseudomonas aeruginosa strain, PAO1. This strain was exposed to sub-lethal doses of lead metal-tdda-phen complexes to form mutants with induced resistance properties with the aim of elucidating their mechanism of action. Various mutations were detected in the mutant P. aeruginosa genome, causing amino acid changes to proteins involved in cellular respiration, the polyamine biosynthetic pathway, and virulence mechanisms. This study provides insights into acquired resistance mechanisms of pathogenic organisms exposed to Cu(II), Mn(II), and Ag(I) complexes incorporating phen with tdda and warrants further development of these potential complexes as alternative clinical therapeutic drugs to treat AMR infections. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00775-022-01979-8.

e21163 Background: CIN can lead to increased patient/healthcare burden, resource utilization, hospitalizations, and poorer quality of life (QoL). G-CSF has a high incidence of bone pain and mild thrombopenia and is given the day after chemo. Plin, a novel non-G-CSF small molecule, protects the bone marrow stem cell, has minimal bone pain, and protects platelet precursors. Plin is given on the same day as chemo and has NSCLC anticancer efficacy (ESMO 2021, Feinstein). The CIN effects of Doc plus Plin vs Doc with Plac were pooled from 3 NSCLC clinical trials. Methods: Data from randomized trials, phase (Ph) 3 trial 103 (NCT02504489), Ph2/3 trial 105 ( NCT03102606 ), and Ph2 trial 101 (NCT00630110) were pooled. Pts were randomized to either Doc (75mg/m2) plus Plin (20mg/m2 or its pharmacokinetic equivalent) (n = 146) or Doc plus Plac (n = 296). Doc was administered on day 1 of each 21-day cycle x 4 cycles, and Plin or Plac was administered ~30 minutes after Doc. Neutrophil counts were taken at predose and day (D) 8 of each cycle in studies 101 & 103, and on predose, D1, 2, 6, 7, 8, 9, 10, 15, and 21 in study 105. Pts given G-CSF in D1-D3 were excluded. Duration of severe neutropenia (DSN) was calculated by methods previously reported (ASH 2022, Blayney). All Grade (Gr) and Gr4 neutropenia (N) rates, Absolute N count (ANC), febrile N (FN) rate, and ANC on D8 (‘nadir’) were obtained. QoL scores were obtained in studies 103 and 105 by EORTC QLQ-C30. Patient-reported adverse events (AEs) were collected. Results: Pt demographics were comparable. Plin was statistically and clinically significantly superior to Plac for All Gr and Gr4 N frequencies, Day 8 ANC (‘nadir’), and DSN (all had p < 0.0001). Febrile Neutropenia (FN) and infection rates were numerically lower (see table). Fewer pts were treated with antibiotics among pts treated with Plin. Platelet count was unaffected with Plin; grade (gr) 3/4 thrombocytopenia was < 1% with either Plin or Plac. The total frequency of treatment-emergent AEs for Plin vs Plac were 71% vs 80%. QoL scores were similar for Plin and Plac. Conclusions: In 3 independent randomized studies (101, 103, and 105), Plin demonstrated a superior benefit for CIN and showed clinical benefit for infection rate versus Plac. Additionally, Plin has the added benefits of pt convenience (same-day dosing and no additional visits or wearable device), a favorable safety and tolerability profile, anticancer efficacy, and QoL maintenance, which represents a distinct advantage over G-CSF. Clinical trial information: NCT02504489 ; NCT03102606 ; NCT00630110 . [Table: see text]