Send Orders for Reprints to [email protected] 305 Current Topics in Medicinal Chemistry, 2017, 17, 305-318 REVIEW ARTICLE ISSN: 1568-0266 Volume 17, Number 3 eISSN: 1873-5294 Impact Factor: Polymeric Quaternary Ammonium Compounds: Versatile Antimicrobial 2.9 The international journal for in-depth Materials reviews on Current Topics in Medicinal Chemistry BENTHAM SCIENCE Deanna L. Zubris1,*, Kevin P.C. Minbiole1,* and William M. Wuest2,* 1Department of Chemistry, Villanova University, Villanova, PA 19085, USA; 2Department of Chemistry, Temple Univer- sity, Philadelphia, PA 19122, USA Abstract: Polymeric Quaternary Ammonium Compounds (polyQACs) comprise a broad class of ma- terials with applications in medical implants, food processing, and surface sanitizing, amongst many A R T I C L E H I S T O R Y others. These polymeric substances are especially promising due to their potent antibacterial activity Received: May 13, 2015 and limited hemolytic toxicity. In particular, many polyQACs have superior therapeutic indices and a Revised: June 10, 2016 Accepted: August 10, 2016 lower likelihood of developing antibacterial resistance in comparison to their monomers, making them ideal materials for wound dressings, catheters, and other biomedical applications. This review DOI: 10.2174/15680266166661608291 55805 outlines the history and development, previous successes, current state of the research, and future di- rections of polyQACs in society. Keywords: Antimicrobial activity, Biofilm, Cationic polymers, Copolymer, Homopolymer, Hydrogel, Polyquaternium, Qua- ternary ammonium compound. A. BACKGROUND ON POLYQACS Another approach to QAC development has been in the field of polymeric QAC structures (polyQACs), which show 1. Introduction promise to address two limitations of monomeric QAC struc- The pathogenic capabilities of bacteria have been known tures – the need for removal from surfaces to minimize tox- for centuries; addressing this scourge has led to some of the icity [9], and well as the need for reapplication to maintain greatest advances in human health. For example, the im- efficacy. It is estimated that over 500,000 tons of QACs are provement of hygiene and development of antibiotics have applied annually; approximately 75% of this total advances led to the saving and improvement of innumerable lives. For to wastewater treatment facilities, while the remainder enters nearly a century, antibiotics have provided crucial protection the environment [10]. This leads to continuous exposure of to humans, despite their inevitable capitulation to the relent- bacteria to sublethal QAC levels, which corresponds to an less advance of bacterial evolution. Hygienic advances have increase in QAC resistant bacteria found in the environment corresponded to increased lifespan for an even longer seg- and in medical settings [11-15]. PolyQACs, whose one-time ment of human history, as modern sanitation and the fre- application would greatly diminish the environmental foot- quent use of soaps, detergents, and antimicrobials have be- print, may address some of these issues. come ubiquitous [1]. Antimicrobial agents, perhaps owing to There are additional reported advantages that polyQACs their widely ranging structural classes and oftentimes-simple possess over their monomeric counterparts. Some poly- preparation, have been a key field of innovation for scientists QACs have been shown to have a low propensity for bacte- and health professionals. rial resistance [16]. Also, it has been observed that a strain of One of the longest-serving classes of antimicrobial com- Pseudomonas aeruginosa that was non-susceptible to QACs pounds is quaternary ammonium compound (QACs), which in solution was killed upon adhesion to a coating of immobi- have seen use in pre-surgical sanitizing since the 1930s [2]. lized QACs, which suggests a different mechanism of antim- The development and widespread utilization of formulations icrobial action for polyQACs [17]. Furthermore, it has been such as benzalkonium chloride have paved the way for many noted that polyQACs often retain their antimicrobial activity incremental advances of QACs, which by some reckonings even after adsorption of proteins [18] or under in vivo condi- are into their sixth generation [3, 4]. Since these “genera- tions [19]. tions” often comprise only modest structural variations, or The incorporation of antimicrobial functionality into represent co-formulations of previous structural classes, ma- polymers has the possibility to address another problem that jor structural advances have been slow to reach the market- has persistently nagged monomeric QACs – their diminished place, and leave this field ripe for innovation [5-8]. ability to disrupt bacteria in the biofilm state. Biofilms, es- tablished communities of bacteria that form a protective ma- *Address correspondence to this author at the Department of Chemistry, Villanova University, Villanova, PA 19085, USA; Tel: 610-519-4874; Fax: trix composed of extracellular materials to defend the popu- 610-519-7167; E-mail: [email protected] lation against environmental threats, can be 100-1000x less 1873-5294/17 $58.00+.00 © 2017 Bentham Science Publishers Current Topics in Medicinal Chemistry 306 Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 3 Zubris et al. susceptible to antibiotic and antiseptic treatments [20]. often called into question. Studies indicate that the antimi- Biofilms are associated with over 80% of microbial infec- crobial agents on surfaces can work differently from those in tions [21], and are often associated with indwelling medical solution [54]; molecular targets are generally not specified, devices such as catheters and joint replacements. Addition- though membrane disruption is likely [40]. Two key reviews ally, most materials are susceptible to biodegradation in the set out to discuss such issues – both a book chapter [55] and presence of microbial biofilms [22]. Thus antimicrobial ma- a detailed report from the Baxter Healthcare laboratories terials that display an inherent resistance to bacterial attach- [56]. At the heart of the problem is the differentiation of ac- ment could show significant advantage over traditional mate- tivity derived from the leaching of monomeric species away rials. The design of surfaces or coatings that either repel from polymeric structures; zone of diffusion tests are quite bacterial attachment or that kill microbes on contact has been commonplace in this arena, despite the obvious concerns of demonstrated [23], although much remains to be done in such an approach for polymer bioevaluation. Alternatives for order to significantly improve medical applications such as efficacy testing can take many forms, with effective methods indwelling devices [24]. reported for immersive or direct inoculation, surface growth Reports of polyQAC structures appeared as early as 1958 methods, and luminescent signaling. [25], with a slow trickle of reports and patents emerging over The ASTM has developed a standardized method for the the next decade [26-29]. The antimicrobial activity of poly- immersive antimicrobial testing of immobilized structures mers was first reported in 1965, as was an early indication of (ASTM E2149) [57], which measures colony-forming units the superior activity of one polymer over its corresponding (CFU) that can grow from a liquid bacterial culture that has monomer, in a polymerized tropone system [30, 31]. In been exposed to the immobilized antimicrobial agent. This 1971, these two fields definitively met when Panarin and test has been adopted somewhat routinely [58, 59]. This coworkers described the polymerization of (2- method, however, can have confounding factors, including methacryloxyethyl)-triethylammonium iodide or bromide, as the adhesion of cells to and the leaching of compounds from well as the synthesis of copolymers with N-vinylpyrrolidone; the polymer surface. Testing to failure (i.e., pushing to see a antimicrobial activity of this polyQAC was also reported maximum number of cells killed per unit area of polymer) is [32]. This field began to flourish over the next decade, start- both informative and recommended [55]. ing with reports on the bioactivity of QAC ionenes (poly- Direct inoculation is another testing strategy that involves mers having ionic groups as part of the main chain) by Rem- the placement of a small amount of a bacterial culture di- baum [33, 34] and Samour [35]. The stage had been set for rectly onto the antimicrobial surface, followed by spreading significant structural variation of polyQACs as well as multi- of the inoculum with a coverslip; the Japanese Industry fold biological applications thereof. Standard method (JIS Z-2801) is commonly adopted for this use [60]. After a designated inoculation time, the assembly is 2. Previous Reviews disassembled and agitated, and the surviving bacteria are An abundance of reviews have been reported in the sepa- assessed as CFUs. Concerns have been raised, however, with rate fields of antimicrobial polymers, as well as antimicro- the likelihood of cell adhesion to the coverslip; agitation may bial QACs. For example, Fernandez-Garcia recently pro- release unaffected cells back to the inoculum and skew re- vided an extensive review of polymeric materials with an- sults [55]. timicrobial activity [36], and subsequently edited a book on As an interesting alternative, methods have been devel- the same topic [37]. Related reviews were reported by Khan oped to deliver a uniform layer