1,540 Australian soldiers were given an unregistered antimalarial. 1,157 more got six times the approved mefloquine dose. No follow-up was ever done.

Arylamino alcohols constitute an established class of antimalarial agents. While this class is best known for its potent antiplasmodial activity, selected members, most notably mefloquine, have also been reported to exhibit antibacterial activity. Structurally related 3-hydroxypropanamidines were developed as highly potent antimalarial agents. Here, we explored the antibacterial activity of three 3-hydroxypropanamidines (4 (BLK278), 5 (BLK280), and 6 (TKK088)) against clinically relevant Gram-positive and Gram-negative bacteria and investigated their cytotoxicity, in vitro pharmacokinetic properties, and proteome-based bacterial response to treatment. We observed good antibacterial activity against Staphylococcus aureus, with 6 (TKK088) displaying the highest activity against multidrug-resistant MRSA and VISA strains. 5 (BLK280) demonstrated the greatest spectrum of activity acting also against clinically relevant Gram-negative strains of Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Klebsiella aerogenes, and Shigella sonnei. In cytotoxicity assays with HUVEC and HAOSMC cells, 4 (BLK278) and the previously reported 7 (TKK129) showed the most favourable overall profiles among the investigated 3-hydroxypropanamidines. The selectivity indices for S. aureus were below 2.5 with clear cell-type-dependent differences for all compounds including mefloquine, suggesting that improving antibacterial selectivity is an important objective for further optimization. In vitro pharmacokinetics showed high plasma protein binding and good human microsomal and plasma stability for all three 3-hydroxypropanamidines. Gel-based proteomic responses revealed a strong impact on the bacterial cell envelope. The observed acute proteomic responses reflect pleiotropic effects and are consistent with earlier reports implicating F0F1-ATPase as a potential molecular target of mefloquine in Streptococcus pneumoniae.

Arylamino alcohols constitute an established class of antimalarial agents. While this class is best known for its potent antiplasmodial activity, selected members, most notably mefloquine, have also been reported to exhibit antibacterial activity. Structurally related 3-hydroxypropanamidines were developed as highly potent antimalarial agents. Here, we explored the antibacterial activity of three 3-hydroxypropanamidines (4 (BLK278), 5 (BLK280), and 6 (TKK088)) against clinically relevant Gram-positive and Gram-negative bacteria and investigated their cytotoxicity, in vitro pharmacokinetic properties, and proteome-based bacterial response to treatment. We observed good antibacterial activity against Staphylococcus aureus, with 6 (TKK088) displaying the highest activity against multidrug-resistant MRSA and VISA strains. 5 (BLK280) demonstrated the greatest spectrum of activity acting also against clinically relevant Gram-negative strains of Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Klebsiella aerogenes, and Shigella sonnei. In cytotoxicity assays with HUVEC and HAOSMC cells, 4 (BLK278) and the previously reported 7 (TKK129) showed the most favourable overall profiles among the investigated 3-hydroxypropanamidines. The selectivity indices for S. aureus were below 2.5 with clear cell-type-dependent differences for all compounds including mefloquine, suggesting that improving antibacterial selectivity is an important objective for further optimization. In vitro pharmacokinetics showed high plasma protein binding and good human microsomal and plasma stability for all three 3-hydroxypropanamidines. Gel-based proteomic responses revealed a strong impact on the bacterial cell envelope. The observed acute proteomic responses reflect pleiotropic effects and are consistent with earlier reports implicating F0F1-ATPase as a potential molecular target of mefloquine in Streptococcus pneumoniae.

Breached is passionate about alleviating moral injury and ethical injustice in armed forces personnel, including veterans and their support circles. As daughters of British nuclear test veterans, we ...

Song · 1992 · Duration 6:14

Malaria, caused by the parasite Plasmodium falciparum, remains a significant global health threat, with multidrug resistance posing a major challenge to treatment. The P-glycoprotein homolog P. falciparum Multidrug Resistance Protein 1 (PfMDR1) is a key determinant of resistance to first-line antimalarials like mefloquine (MFQ) and chloroquine. ACT-451840, a clinical phase I drug, has been developed as an antimalarial candidate, but its mechanism of action and interaction with drug resistance markers remain to be fully understood. Here, we present the cryo-electron microscopy structure of PfMDR1 in complex with ACT-451840, determined at a resolution of 3.42 Å. The structure reveals that ACT-451840 binds within the central cavity and locks PfMDR1 in an inward-open conformation, inhibiting its basal ATPase activity. A structural comparison of the ACT-451840-bound state with the previously reported MFQ-bound state provides a molecular explanation for how ACT-451840 resistance mutations ca

Learn about the link between malaria medications and veteran health issues, including the use of mefloquine.

For much of the 1990s and early 2000s, the U.S. military issued mefloquine (Lariam) as a standard prophylactic against malaria for deployed service members. It was cheap, required only weekly dosing, ...