Shifting from Ammonium to Phosphonium Salts: A Promising Strategy to Develop Next-Generation Weapons against Biofilms

Abstract

Since they are difficult and sometimes impossible to treat, infections sustained by multidrug-resistant (MDR) pathogens, emerging especially in nosocomial environments, are an increasing global public health concern, translating into high mortality and healthcare costs. In addition to having acquired intrinsic abilities to resist available antibiotic treatments, MDR bacteria can transmit genetic material encoding for resistance to non-mutated bacteria, thus strongly decreasing the number of available effective antibiotics. Moreover, several pathogens develop resistance by forming biofilms (BFs), a safe and antibiotic-resistant home for microorganisms. BFs are made of well-organized bacterial communities, encased and protected in a self-produced extracellular polymeric matrix, which impedes antibiotics’ ability to reach bacteria, thus causing them to lose efficacy. By adhering to living or abiotic surfaces in healthcare settings, especially in intensive care units where immunocompromised older patients with several comorbidities are hospitalized BFs cause the onset of difficult-to-eradicate infections. In this context, recent studies have demonstrated that quaternary ammonium compounds (QACs), acting as membrane disruptors and initially with a low tendency to develop resistance, have demonstrated anti-BF potentialities. However, a paucity of innovation in this space has driven the emergence of QAC resistance. More recently, quaternary phosphonium salts (QPSs), including tri-phenyl alkyl phosphonium derivatives, achievable by easy one-step reactions and well known as intermediates of the Wittig reaction, have shown promising anti-BF effects in vitro. Here, after an overview of pathogen resistance, BFs, and QACs, we have reviewed the QPSs developed and assayed to this end, so far. Finally, the synthetic strategies used to prepare QPSs have also been provided and discussed to spur the synthesis of novel compounds of this class. We think that the extension of the knowledge about these materials by this review could be a successful approach to finding effective weapons for treating chronic infections and device-associated diseases sustained by BF-producing MDR bacteria.

Anti Gram-Positive Bacteria Activity of Synthetic Quaternary Ammonium Lipid and Its Precursor Phosphonium Salt

“…QASs demonstrated considerable broad-spectrum potency against Gram-positive and Gram-negative bacteria and some fungi [ 3 ]. Conventional QASs contain one or more positively charged nitrogen atoms (N + ), which constitute the cationic head, and which can be inserted either in the aromatic ring of pyridine, imidazole, quinoline, and isoquinoline or in a straight alkyl chain [ 4 ]. The N + covalently binds four carbon atoms, of which at least one belongs to a C8–C18 alkyl chain, resembling the chains of fatty acids [ 4 ].…”

“…Conventional QASs contain one or more positively charged nitrogen atoms (N + ), which constitute the cationic head, and which can be inserted either in the aromatic ring of pyridine, imidazole, quinoline, and isoquinoline or in a straight alkyl chain [ 4 ]. The N + covalently binds four carbon atoms, of which at least one belongs to a C8–C18 alkyl chain, resembling the chains of fatty acids [ 4 ]. QASs are water-soluble due to their hydrophilic ammonium head, which has a chloride (Cl − ) or bromide (Br − ) atom as an anion.…”

“…Whereas, thanks to their long alkyl chain representing their hydrophobic (nonpolar) part, QASs can penetrate the nonpolar cell membrane, thus altering its permeability and leading to bacterial death [ 2 ]. Specifically, after absorption on the bacterial surface, by intercalating with the membranes and altering their normal structure, QASs succeed in modifying membrane permeability by pore formation, thus determining the loss of enzymes, coenzymes, and ions and compromising the biosynthetic activities of bacteria, triggering their death [ 3 , 4 , 6 ]. Interestingly, such mechanisms have little effect on the resistance and sensitivity of bacteria [ 7 ].…”

“…As recently reported, QASs could comprehend single-chain QASs, double-chain QASs, heterocyclic QASs [ 10 ], gemini QASs [ 11 ], and QASs with more than two positively charged moieties, depending on the number and structure of their long carbon chains and on the number and typology of their cationic heads [ 2 , 4 ]. Single-chain QASs are simply structured possess good antibacterial effects, and a wide range of antibacterial applications have been reported [ 12 ].…”

“…Seddon and co-workers reported a series of tetra-alkyl phosphonium salts and studied their antimicrobial activity against several bacterial and fungal strains, observing an antibacterial activity depending on the length of the alkyl chains and the type of anion [ 22 ]. Interestingly, studies of comparison between QASs and QPSs showed that the latter possess antimicrobial activity higher than that of polymeric quaternary ammonium salts because of a difference in electronegativity between nitrogen and carbon atoms and phosphorous and carbon atoms [ 4 , 23 ]. Additionally, studies have shown that by replacing the cationic ammonium groups of QASs with phosphonium ones as in QPSs, phosphonium lipids with significantly lower cytotoxicity than the quaternary ammonium analogues can be developed [ 5 ].…”