Nanotechnology Formulations for Antibacterial Free Fatty Acids and Monoglycerides


Antibiotic resistance is one of the most serious public health issues in the world, sparked in part by the overuse of antibiotics in medicine and agriculture [1]. In the face of multidrug-resistant bacteria, many antibiotics are losing effectiveness, and there is growing recognition that a post-antibiotic era is approaching [2]. Antibiotics are a key sector of the pharmaceutical industry, as evidenced by high annual expenditures of up to US $10.7 billion in the United States alone [3,4]. The majority of the expenditure comes from outpatient drug prescriptions [4]. The widespread prescription of antibiotics, especially in the outpatient setting, inevitably results in the rise of multidrug-resistant bacterial strains. In recent years, there has been growing recognition of the rise in multidrug-resistance among various bacterial strains as a major public health crisis [5]. Antibiotic-resistant bacterial strains have been estimated to affect 2 million patients annually in the European Union alone [6]. Meanwhile, in the United States, antibiotic-resistance costs more than US $20 billion per year as well as an additional one to two weeks of inpatient care per patient, which strains the existing medical infrastructure [6].
The antibiotic-resistance problem is further aggravated by the fact that new antibiotic drug development has lagged behind the evolution of antibiotic-resistant bacterial strains. From the 1960s up through 2011, merely four new classes of antibiotics were successfully developed and marketed [6]. A 2013 study revealed that only four large pharmaceutical companies have active R & D programs to develop new antibiotics, as compared to 20 companies in the 1980s [3]. Aside from the scientific difficulty in developing new antibiotics, the lack of new antibiotics has been attributed to a perceived lack of potential profit due to competition from low cost, off-patent generic drugs and the short-course nature of antibiotic treatment. Historically unfavorable regulations and policies by government agencies such as the United States Food and Drug Administration (FDA) have also been cited as a factor which discourages the development of new antibiotics [7]. There are increasing demands for narrow-spectrum antibiotics with focused activity against specific bacteria in order to mitigate the chance for antibiotic-resistant bacterial strains to emerge [8]. Broad-spectrum antibacterials with targets that have very high barriers to generating resistance mutations are also in great demand.
Recently, there has been serious attention directed to this issue because the number of drug-resistant bacteria, or so-called super bacteria, continues to rise unabated [9,10]. There is even growing discussion about the end of the antibiotic era altogether. In order to encourage the development of new antibiotics, the FDA has created a new product category called the Qualified Infectious Disease Product (QIDP) [11]. Drugs in this category have a special designation from the FDA, which shortens the approval review process and increases the time (an additional 5 years) for exclusive marketing. These benefits are important because it means that new antibiotics can reach patients more quickly, and there is more economic motivation for pharmaceutical companies to develop new antibiotics. In turn, there has been a positive rise in the number of new antibiotics in the past two years [12]. However, nearly all of these newly approved antibiotics are in fact derivatives of existing antibiotics and share overlapping mechanisms of action. Hence, the problem of drug-resistance quickly emerging is not avoided but rather prolonged, and there is a need for antibiotics against novel bacterial targets, especially those with very high barriers to mutation.
In this regard, membrane-active antibacterial agents hold significant promise [13]. Importantly, the development of resistant bacterial strains against membrane-active compounds has low frequency because there is a high barrier to mutation of the bacterial cell envelope [14]. Membrane-active peptides emerged as an attractive contender and can have potent antibacterial activity [15]. There are many academic studies on membrane-active antibacterial peptides and a few candidates have even reached clinical trials (with at least one in Phase III trials) in the late 90s [16,17]. However, a particularly stringent FDA approval process at the time led to the lack of approval for peptide candidates of that era, and there was a concomitant push in the biotechnology industry at large to move beyond peptide therapeutics [18]. In addition, there are common technical issues with most membrane-active peptides, including weak performance in physiological salt conditions [19], cationic character often renders them toxic to human cells [20], and typical dependence on amino acid secondary structure which is sensitive to environmental conditions. Moreover, membrane-active peptides can be costly to produce [17].
At the same time, there is already a documented solution—naturally abundant and low cost free fatty acids and monoglycerides (so-called antimicrobial lipids) with broad-spectrum antibacterial activity—which has long been known, yet was cast aside in favor of small molecule antibiotics for the past few decades [21]. With the current challenges in antibiotic drug development, antimicrobial lipids deserve renewed attention and represent potential solutions to the problem of drug-resistant bacteria. The potential of free fatty acids for biotechnology applications has been highlighted in at least two reviews in the past six years [22,23]. However, arguably the greatest potential for antimicrobial lipids, including free fatty acids, lies in nanotechnology formulations which take advantage of the potent antibacterial properties of these compounds while improving their pharmacological properties and providing superior delivery vehicles. Indeed, these efforts fall under the concept of nanoarchitectonics, an emerging set of design guidelines to incorporate functional molecules into application-oriented nanostructures [24,25,26,27]. In recent years, there have been extensive efforts to achieve the goal of establishing nanotechnology formulations for antimicrobial lipids, yet the collection of research efforts towards this goal has not been summarized.
The aim of this review is to introduce antimicrobial lipids as a class of potent antibacterial agents and to highlight emerging nanotechnology formulations of fatty acids and monoglycerides. An overview of antimicrobial lipids is first provided, followed by a detailed description of formulation strategies based on nano-emulsions, liposomes, solid lipid nanoparticles, and controlled release hydrogels. Finally, the application potential of the nanotechnology formulations is discussed in the context of developing effective solutions to drug-resistant bacteria.

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