{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T12:43:32Z","timestamp":1759495412463,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background\/Objectives: Malaria remains the most critical parasitic disease globally, responsible for over 600.000 deaths annually. In sub-Saharan Africa, co-infections of Plasmodium falciparum with other pathogens, particularly Staphylococcus aureus, are common in children with severe malaria. Therefore, the design of new compounds targeting both pathogens appears to be an urgent priority. Methods: A small series of hybrid compounds was designed and synthesized by linking the pharmacophore of the antimalarial drug chloroquine with the phenothiazine core. These compounds were tested in vitro against a panel of microbial strains and further analyzed through in silico simulations to predict their physical-chemical properties. Results: Compounds 4b and 5b emerged the most potent candidates of the series, showing a sub-micromolar inhibitory activity on P. falciparum, and a promising micromolar potency on S. aureus alongside with a low toxicity on mammalian cells. Molecular docking followed by molecular dynamics (MD) simulations identified the respiratory membrane NDH-2 enzyme as common target in both pathogens. Conclusions: Both experimental and computational findings provide compelling evidence for the use of the designed compounds in a STOP strategy, i.e., Same-Target-Other-Pathogen, to treat malaria and bacterial infections concurrently.<\/jats:p>","DOI":"10.3390\/antibiotics14100991","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T11:53:37Z","timestamp":1759492417000},"page":"991","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["STOP Strategy to Inhibit P. falciparum and S. aureus Growth: Molecular Mechanism Studies on Purposely Designed Hybrids"],"prefix":"10.3390","volume":"14","author":[{"given":"Beatrice","family":"Gianibbi","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4903-6944","authenticated-orcid":false,"given":"Riccardo","family":"Corina","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9030-1066","authenticated-orcid":false,"given":"Nicoletta","family":"Basilico","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Surgical and Dental Sciences, Universit\u00e0 degli Studi di Milano, Via Carlo Pascal, 36, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0263-7107","authenticated-orcid":false,"given":"Ottavia","family":"Spiga","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9044-5377","authenticated-orcid":false,"given":"Silvia","family":"Gobbi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6365-5579","authenticated-orcid":false,"given":"Federica","family":"Belluti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna Angela","family":"Gentilomi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Massarenti 9, 40138 Bologna, Italy"},{"name":"Microbiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Massarenti 9, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2079-8892","authenticated-orcid":false,"given":"Silvia","family":"Parapini","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences for Health, Universit\u00e0 degli Studi di Milano, Via Carlo Pascal, 36, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8101-9835","authenticated-orcid":false,"given":"Francesca","family":"Bonvicini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Massarenti 9, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4662-4743","authenticated-orcid":false,"given":"Alessandra","family":"Bisi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1021\/acsinfecdis.3c00189","article-title":"Small-Molecule Antibiotic Drug Development: Need and Challenges","volume":"9","author":"Bergkessel","year":"2023","journal-title":"ACS Infect. 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