Potential Applications of Antimicrobial Fatty Acids in Medicine, Agriculture | Antimicrobial | Antibiotics

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Potential Applications of Antimicrobial Fatty Acids in Medicine, Agriculture
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   Recent Patents on Anti-Infective Drug Discovery, 2012, 7  , 111-122111  2212-4071 /12 $100.00+.00 © 2012 Bentham Science Publishers Potential Applications of Antimicrobial Fatty Acids in Medicine, Agriculture and Other Industries Andrew P. Desbois* Marine Biotechnology Research Group, Institute of Aquaculture, School of Natural Sciences, University of Stirling, Stirlingshire, FK9 4LA, UK  Received: April 5, 2012; Revised: May 4, 2012; Accepted: May 5, 2012 Abstract: The antimicrobial effects of free fatty acids are well recognised and these compounds can prevent the growth of or directly kill bacteria, fungi and other microbes by affecting multiple cellular targets, including the cell membrane and components found therein. Moreover, fatty acids exert detrimental effects on microbial pathogens by interfering with mechanisms of virulence, such as preventing biofilm formation and inhibiting the production of toxins and enzymes. The antimicrobial properties of free fatty acids can be exploited for the preservation of perishable products, such as food and cosmetics, and for the prevention and treatment of infections. These safe natural products are particularly useful in cir-cumstances where antimicrobial activity is required but where the use of conventional antibiotics is undesirable or forbid-den. This review focuses on the most promising prospects for exploiting the antimicrobial properties of free fatty acids for applications in various industries. The benefits of using fatty acids as antimicrobial agents are discussed and relevant re-cent patents are highlighted. Keywords: Antibacterial, antifungal, decolonisation, disinfectant, growth promoter, lauric acid, mastitis, wound therapy. INTRODUCTION The antimicrobial properties of fatty acids have been recognised for decades [1, 2], and these compounds function in the innate immunity of humans and animals to defend against microbial opportunists, particularly on mucosal sur-faces and the skin [3-12]. Similarly, fatty acids function in the defences of algae and plants to protect against pathogens and undesirable colonisers [2, 13, 14]. Despite well docu-mented antimicrobial attributes, fatty acids have been rela-tively under exploited in commercial products and applica-tions where these properties are important. Thormar [1] at-tributed this in part to the discovery of conventional antibiot-ics from bacteria and fungi in the 1940s because these com- pounds show greater potency and selectivity than fatty acids. However, there is now broad acceptance for the continual need to discover and develop new antimicrobial compounds due to the evolution of microbial resistance to contemporary agents, especially for the treatment of drug-resistant human infections [15, 16]. In addition, the use of conventional anti- biotics is undesirable or banned in certain instances meaning that alternatives are urgently required. Against this backdrop, there is strong justification for evaluating and re-evaluating free fatty acids as potential antimicrobial agents for a variety of medicinal, agricultural and industrial applications [7]. This present article discusses the benefits of using free fatty acids as antimicrobials and highlights selected recent patents and patent applications of significance in this field. *Address correspondence to this author at the Marine Biotechnology Re-search Group, Institute of Aquaculture, School of Natural Sciences, Univer-sity of Stirling, Stirlingshire, FK9 4LA; Tel: +44 (0)1786 467894; Fax: +44 (0)1786 472133; E-mail: ad54@stir.ac.uk BENEFITS OF USING ANTIMICROBIAL FATTY ACIDS There are numerous benefits for incorporating fatty acids into products for their antimicrobial properties (Table 1 ). Typically, fatty acids demonstrate a broad spectrum of an-timicrobial action and these compounds can exert antagonis-tic effects against Gram-positive and Gram-negative bacte-ria, mycobacteria, Archaea, filamentous fungi and yeast, enveloped viruses, protozoa and eukaryotic algae [2, 7, 17-25]. As a result, fatty acids are potentially valuable antimi-crobial agents for diverse biotechnological applications, es- pecially in circumstances where it is important to affect a diverse range of microbes. Notably, the saturated fatty acids capric acid (C10:0) and lauric acid (C12:0) seem to show the  broadest spectra of antimicrobial activities [2, 3, 24, 26]. In many cases, free fatty acids exert their antimicrobial effects at micro- to millimolar concentrations [7, 27], which are often below doses causing toxicity to non-target cells and tissues [10, 25, 28, 29]. Chemically, fatty acids are relatively stable [30], but they do degrade naturally and are bioaccu-mulated relatively quickly meaning that they pose little or no risk as environmental toxins [2, 24]. Many fatty acids are commercially available in highly pure preparations from natural sources, but others can be produced synthetically with relative ease. The mechanism of antimicrobial action by fatty acids can  be inhibitory or cidal and this depends on many factors, in-cluding the fatty acid under investigation and its concentra-tion, the target microbe and its physiological state, and the  physiological conditions associated with delivery and inter-action with the microbial cell (e.g., pH and temperature) [28, 31-39]. In cidal interactions, the time it takes to kill the  112  Recent Patents on Anti-Infective Drug Discovery, 2012  , Vol. 7, No. 2 Andrew P. Desbois microbe can vary from immediate mortality to far longer  periods before death ensues [31, 39, 40-43]. Importantly, antimicrobial fatty acids act on a range of cellular targets and  by various mechanisms (reviewed by Desbois and Smith [2 however, often the principal target is the cell membrane and a range of components located therein, including pro-teins involved in nutrient uptake and other pores and en-zymes [24, 34, 44, 45]. Fatty acids can disrupt the integrity of the cell membrane in various ways, which can lead to the leakage of important cellular metabolites and even cell lysis [2, 24, 34, 44]. Moreover, fatty acids can interfere with nu-trient uptake and energy generation by electron transport and oxidative phosphorylation that occurs in the cell membranes of bacteria and the mitochondrial membranes of eukaryotic microbes [23, 45-48]. Aside from perturbation of mem- branes, fatty acids can interact with other intracellular targets and enzymes, including those involved in fatty acid synthesis [2, 22, 24, 49, 50]. Free fatty acids can exert a protonophore effect, whereby the pH of the cytoplasm is reduced to such an extent that the cell ceases to function normally [47, 48]. That fatty acids act on multiple cellular targets means that the selection of resistance is expected to be rare [35, 40, 51], and no resistant strains were identified amongst a library of 5000 transposon insertion mutants of Staphylococcus aureus [45]. Nevertheless, in some cases reductions in susceptibili-ties of strains to the action of fatty acids has been reported [52], and decreases in the external hydrophobicity of micro- bial cells may diminish the antimicrobial effectiveness of a fatty acid, as this interferes with the initial interaction of the fatty acid and the cell [45, 53, 54]. Similarly, changes in mi-crobial membrane composition may alter cell susceptibility to the actions of fatty acids [32, 34, 53]. Mortensen et al  .[55] also reported that the activity of a bacterial enzyme (called fatty acid modifying enzyme) could inactivate antim-icrobial fatty acids by esterifying these compounds to certain alcohols. Besides direct antimicrobial effects on growth and mor-tality, fatty acids can be detrimental for microbes by indirect mechanisms, such as affecting a microbe’s ability to colonise or exploit a host or surface. Biofilms allow microbial cells to  persist on biological or inanimate surfaces and these struc-tures are known to play vital roles in many diseases and in-fections [56]. However, free fatty acids can prevent biofilm formation by interfering with adhesion or disrupting micro- bial cell-to-cell communications [23, 57-59]. Interestingly, 2-decylenic acid (C10:1n-8) can induce the dispersal of cells from biofilms formed by various bacteria and fungi [60]. Aside from anti-biofilm properties, fatty acids exhibit other anti-virulence bioactivities. The swarming characteristic of  Proteus mirabilis  (a urinary tract pathogen) is important for the colonisation of artificial surfaces such as catheter tubes, and this behaviour occurs in synchrony with the expression of specific virulence factors [61]. However, certain medium- and long-chain saturated free fatty acids such as C12:0 pre-vent the swarming phenotype in  P. mirabilis  and the expres-sion of the associated virulence factors, including haemo-lysin [61]. In addition, microbial toxins are down-regulated in other pathogens in the presence of free fatty acids, includ-ing the toxic shock syndrome toxin-1 of S. aureus  that is down-regulated by C12:0 [62]. Furthermore, the expression of enzymes that confer drug resistance such as -lactamase are down-regulated in the presence of various saturated and unsaturated free fatty acids [53, 61, 62]. Iron acquisition and the production of proteases and other enzymes are important  processes during the exploitation of a host but the expression of these virulence factors or their activities may be reduced Table 1. Chemical and biological properties of antimicrobial free fatty acids that may be beneficial for particular applications. Potential beneficial attributes of antimicrobial fatty acids Reference(s) Broad spectra of antimicrobial activities [2, 3, 24, 26] High potencies, typically antimicrobial at micro- and millimolar concentrations [7, 27] Microbial resistance rarely selected [35, 40, 45, 51]  Negative effects on the dissemination of microbial virulence factors and their expression [23, 27, 57-61, 63, 65] Low environmental impact [2, 24] Synergies with other antimicrobial agents [53, 74, 75, 77]  Non-irritating at efficacious concentrations [29, 68, 69] Low toxicities to non-microbial cells [10, 25, 28, 29] Relatively stable [30] Exert other favourable non-antimicrobial bioactivities [53, 78-84] Greater antimicrobial efficacy at lower pH [35, 37, 38]  Non-corrosive [66, 67] These properties must be assessed for each individual fatty acid.   Antimicrobial Fatty Acids Recent Patents on Anti-Infective Drug Discovery, 2012  , Vol. 7, No. 2 113  by exposure to fatty acids [45, 57, 63]. Certain fatty acids retard germination and hyphal formation in fungi, which is a crucial physiological process during the progression of many infections, particularly those caused by Candida albicans [27, 64]. Importantly, some free fatty acids such as linoleic acid (C18:2n-6) prevent conjugation between bacteria, and thus the potential transmission of drug resistance genes, which may reduce the spread of clinically important resis-tances [65]. A further benefit to using fatty acids as antimicrobial agents is that these compounds are non-corrosive compared to many commercially available disinfectants that often rely on phenol and chlorine chemistry [66, 67], which means that they can be used safely to disinfect sensitive equipment. Similarly, many disinfectants should not be applied to skin, open wounds or mucosa because they can irritate, cause damage or prevent healing; however, fatty acids are typically non-irritating to human skin at concentrations necessary for antimicrobial efficacy [29, 68, 69]. Besides this, unsaturated C16 and C18 fatty acids are major contributors to the skin’s natural defences against microbial pathogens [6, 70], and so augmentation of these innate defences with the application of additional fatty acids might be expected to have few harmful side effects. Nevertheless, some studies have identified cyto-toxic properties associated with some fatty acids [36, 67, 71] meaning that toxicity should be evaluated for each intended application. Interestingly, fatty acids can demonstrate considerable synergy with other antimicrobial compounds, including con-ventional antibiotics, lysozyme, surfactants and antimicro- bial peptides (AMPs) [53, 72-75]. A synergistic interaction is one in which the efficacy of the combination exceeds the expected cumulative efficacy of the individual components alone. Indeed, free fatty acids found on the surface of human skin synergise with AMPs, which can lead to an enhance-ment of the observed antimicrobial activity [73]. With syn-ergistic combinations reduced quantities of each component are required for the same magnitude of antimicrobial effect, and this may be beneficial because it may be possible to re-duce the severity of harmful side effects caused by poten-tially toxic antibiotics. The use of combinations of agents may also reduce the opportunity for microbial resistance to arise provided that the agents act on distinct cellular targets, as to prosper the microbe must evolve resistances to both agents simultaneously, which is less likely to occur than against a single compound [76]. If desired, combinations of different antimicrobial agents can be selected to enhance the overall spectrum of activity of a particular composition. No-tably, certain combinations of fatty acids demonstrate re-duced melting points (and effectively increased solubility in water) compared to each fatty acid individually, and this may  be important in situations where activity is necessary at low temperatures or in aqueous milieus [77]. Significantly, aside from their direct antimicrobial prop-erties and abilities to temper microbial virulence, many fatty acids demonstrate additional important bioactivities that may  be exploited and thus increase their attractiveness as antimi-crobial agents for particular applications. Such additional  positive characteristics include anti- or pro-inflammatory effects and the promotion of wound healing [53, 78-86]. In summary, though effective concentrations of fatty acids are typically in excess of those necessary for conventional anti- biotics and disinfectants, the use fatty acids for antimicrobial applications is associated with a series of additional potential  benefits. MEDICAL APPLICATIONS OF ANTIMICROBIAL FATTY ACIDS Significant opportunities exist for using antimicrobial free fatty acids to prevent and treat human infections (Table 2 ). There is an urgent need for the discovery, development and introduction of new antibiotics due to the escalating  problem of microbial drug resistance [15, 87]. The antibiotic arsenal available to clinicians is becoming increasingly lim-ited and for certain pathogens only one or two contemporary agents remain effective. Though some studies suggest that free fatty acids may be used to treat systemic infections [28, 53, 88], the most likely prospects for exploiting fatty acids in medicine lie in topical and surface applications, such as the  prevention of microbial colonisation of medical equipment, the decolonisation of drug-resistant pathogens from the skin and noses of hospital patients, and the treatment of microbial infections of the skin, wounds and mucosa [10, 11, 78, 82, 86, 88] (Table 2 ). Indeed, 10-undecylenic acid (C11:1n-1) is already used clinically to treat fungal infections of the skin and nails [89]. Fatty acids may be particularly well-suited for the treatment of superficial skin infections and acne, where the anti-inflammatory properties of certain fatty acids may  provide additional benefits [10] (Table 2 ). Several workers have also pursued fatty acids as agents to treat and prevent the transmission of sexually-transmitted diseases [41, 90], and for the prevention treatment of gum disease, dental car-ies [86, 91, 92] and gastrointestinal infections [35, 51, 93] (Table 2 ). Vogt et al  . [94] describe the invention of antimicrobial surgical sutures that are coated with a fatty acid such as C12:0 in combination with an antiseptic. The fatty acid com- ponent improves the binding efficiency of octenidine dichlo-ride and dequalinium chloride antiseptics to the suture mate-rial, but also it will likely enhance the antimicrobial effec-tiveness of the final coating [94]. Moreover, Roby [95] sug-gests coating sutures and other surgical items with fatty acid esters to hinder bacterial growth, which would be expected to reduce the opportunity for an infection to establish in the healing wound after an invasive procedure. Fatty acids are well-suited as coatings on surgical materials, particularly due to their broad spectrum of potent antimicrobial action and low toxicity, which offer significant advantages over existing  products. Furthermore, implanted medical devices that slowly release beneficial bioactive constituents in vivo are now available [96, 97]. Polypropylene meshes coated with a gel containing a mixture of esterified n-3 fatty acids are used already for hernia repair [96], and bioactive fatty acids are released during natural degradation meaning that these agents are then free to exert antimicrobial and anti-inflammatory activities in vivo [96]. In some countries, nasal decolonisation of methicillin-resistant S. aureus  (MRSA) is performed prior to surgery and this typically involves the use of the topical antibiotic mupi-rocin [98]. Patients receiving mupirocin are at reduced risk  114  Recent Patents on Anti-Infective Drug Discovery, 2012  , Vol. 7, No. 2 Andrew P. Desbois Table 2. Potential applications of antimicrobial fatty acids. Proposed application(s) Reference(s) Recent patent(s) Medical Coating for sutures and surgical equipment to reduce microbial colonisation and/or subsequent infection Franklin et al.  [96] US20080103526 [94]; US6878757 [95] Prevention of gum infections and dental caries Won et al  . [91]; Huang et al  . [92] US20100317734 [77]; US20120029078 [86] Decolonisation of skin pathogens Desbois et al  . [30]; Lacey and Lord [40]; Huang et al  . [69]; Wille and Kydonieus [70] US20100317734 [77] Treatment of acne and skin infections Thormar and Hilmarsson [7]; Chen et al  . [11]; Naka-tsuji et al  . [29]; Yang et al  . [39] US20100317734 [77] Burn and wound therapy Cardoso et al  . [78]; Shingel et al  . [82]; Pieper and Caliri [114] US20100317734 [77] Prevention and treatment of sexually-transmitted diseases Bergsson et al  . [41]; Bergsson et al  . [90] Prevention and treatment of stomach ulcers and gastrointestinal infections Sun et al  . [35]; Petschow et al  . [51]; Sprong et al. [93]; US20100317734 [77]; US20030176500 [124] Treatment of fungal infections Thormar and Hilmarsson [7]; Thibane et al  . [23]; McLain et al.  [27]; Bergsson et al.  [44]; Clément et al  . [64]; Wille and Kydonieus [70]; Hart et al  . [89] US20100317734 [77]; US20080075786 [88] Treatment of lung infections Mil-Homens et al  . [28] Treatment of bacteraemia Clarke et al  . [53] Agricultural Prevention and treatment of fungal diseases of  plants Walters et al  . [117]; Liu et al  . [118] Prevention of foulbrood in honeybees Feldlaufer et al  . [119] Feed preservation US20030176500 [124] Prevention and treatment of mastitis Hogan et al  . [107]; Nair et al  . [108] US7553871 [68]; US7109241 [122]; US6582734 [123] Prevention of hoof infections US7661393 [120] Prevention and treatment of gastrointestinal infections Skivanová et al  . [127] US20030176500 [124] Growth enhancement by altering gut microbiota Dierick et al  . [126] US20030176500 [124]; EP1059041 [125]; US20090285931 [129] Reduction of methane emissions from ruminants Ungerfeld et al  . [19]; Dohme et al  . [128] US20090285931 [129] Disease prevention in aquaculture Desbois et al  . [30]; Benkendorff et al  . [131] Disinfection of animal carcasses Thormar and Hilmarsson [133] US20100317734 [77] Other Surface disinfection Thormar and Hilmarsson [133] US20100317734 [77]; US20080033026 [134] Food preservation Wang and Johnson [33]; Shin et al  . [43]; Sado-Kamdem et al.  [50]; Kristmundsdóttir and Skúlason [85] US20030176500 [124]; US6638978 [132]; US20080033026[134] Preservation of cosmetics and pharmaceuticals Kristmundsdóttir and Skúlason [85] US6638978 [132]; US20080033026 [134]; WO2009072862 [135]
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