molecules Review Amikacin: Uses, Resistance, and Prospects for Inhibition Maria S. Ramirez and Marcelo E. Tolmasky * Center for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-657-278-5263 Received: 27 November 2017; Accepted: 14 December 2017; Published: 19 December 2017 Abstract: Aminoglycosides are a group of antibiotics used since the 1940s to primarily treat a broad spectrum of bacterial infections. The primary resistance mechanism against these antibiotics is enzymatic modification by aminoglycoside-modifying enzymes that are divided into acetyl-transferases, phosphotransferases, and nucleotidyltransferases. To overcome this problem, new semisynthetic aminoglycosides were developed in the 70s. The most widely used semisynthetic aminoglycoside is amikacin, which is refractory to most aminoglycoside modifying enzymes. Amikacin was synthesized by acylation with the L-(−)-γ-amino-α-hydroxybutyryl side chain at the C-1 amino group of the deoxystreptamine moiety of kanamycin A. The main amikacin resistance mechanism found in the clinics is acetylation by the aminoglycoside 60-N-acetyltransferase type Ib [AAC(60)-Ib], an enzyme coded for by a gene found in integrons, transposons, plasmids, and chromosomes of Gram-negative bacteria. Numerous efforts are focused on finding strategies to neutralize the action of AAC(60)-Ib and extend the useful life of amikacin. Small molecules as well as complexes ionophore-Zn+2 or Cu+2 were found to inhibit the acetylation reaction and induced phenotypic conversion to susceptibility in bacteria harboring the aac(60)-Ib gene. A new semisynthetic aminoglycoside, plazomicin, is in advance stage of development and will contribute to renewed interest in this kind of antibiotics. Keywords: aminoglycosides; antibiotic resistance; amikacin; aminoglycoside modifying enzymes; antisense 1. A Brief History of Aminoglycoside Antibiotics Aminoglycosides are a group of antibiotics primarily used to treat a wide spectrum of bacterial infections [1–4]. However, modern medicine has found other uses for these agents that include treatments for various genetic disorders and Meniere’s disease [5–8]. In addition, aminoglycosides are being researched as inhibitors of reproduction of the HIV [3,9]. The general structure of aminoglycosides consists of an aminocyclitol nucleus (streptamine, 2-deoxystreptamine, or streptidine) (Figure1) linked to amino sugars. In addition, there are few exceptions where the antibiotic is considered an aminoglycoside despite not strictly conforming to this rule such as spectinomycin (Figure2), which is an aminocyclitol not bound to amino sugars [ 10]. The first aminoglycoside, streptomycin (Figure2), was discovered in the early days of the antibiotic era (1944) and it is still in use [11,12]. This discovery was followed by those of neomycin (1949) [13,14], and kanamycin (1957) [15] and gentamicin [16,17] (Figure2). Following these findings, other natural aminoglycosides such as tobramycin [18] (Figure2), with robust activity, were discovered. Furthermore, some of them were found to be useful as antifungal and antiparasitic agents [19–22]. For example, paromomycin (Figure2), is used in the treatment of cryptosporidiosis, leishmaniasis, and other infections caused by protozoa and cestodes [20]. All natural aminoglycosides in use to date are produced by soil bacteria Molecules 2017, 22, 2267; doi:10.3390/molecules22122267 www.mdpi.com/journal/molecules Molecules 2017, 22, 2267 2 of 22 Molecules 2017, 22, 2267 2 of 23 are produced by soil bacteria belonging to the genera Streptomyces or Micromonospora, and the origin of each oneMolecules of them 2017, 22is, 2267identified by the suffix, “-mycin” and “-micin”, respectively [23,24].2 of 22 belonging to the genera Streptomyces or Micromonospora, and the origin of each one of them is identified are produced by soil bacteria belonging to the genera Streptomyces or Micromonospora, and the origin by the suffix,of each “-mycin” one of them and is “-micin”,identified by respectively the suffix, “-mycin” [23,24 and]. “-micin”, respectively [23,24]. Figure 1. Chemical structures of aminocyclitols. Figure 1. Chemical structures of aminocyclitols. Figure 2. Chemical structures of representative aminoglycosides. Recent advances have permitted us to understand the biosynthetic pathways of natural aminoglycosides [25]. Unfortunately, as it is the case with all antibiotics, bacteria developed several mechanisms of resistance that threaten the use of these drugs. Aminoglycoside modifying enzymes, which catalyze inactivation by acetylation (aminoglycoside acetyltransferases, AAC), phosphorylation (aminoglycoside phosphotransferases, APH), or adenylylation (aminoglycoside Figure 2. Chemical structures of representative aminoglycosides.aminoglycosides. Recent advances have permitted us to understand the biosynthetic pathways of natural Recent advances have permitted us to understand the biosynthetic pathways of natural aminoglycosides [25]. Unfortunately, as it is the case with all antibiotics, bacteria developed several aminoglycosides [25]. Unfortunately, as it is the case with all antibiotics, bacteria developed mechanisms of resistance that threaten the use of these drugs. Aminoglycoside modifying enzymes, several mechanisms of resistance that threaten the use of these drugs. Aminoglycoside modifying which catalyze inactivation by acetylation (aminoglycoside acetyltransferases, AAC), enzymes, which catalyze inactivation by acetylation (aminoglycoside acetyltransferases, AAC), phosphorylation (aminoglycoside phosphotransferases, APH), or adenylylation (aminoglycoside phosphorylation (aminoglycoside phosphotransferases, APH), or adenylylation (aminoglycoside Molecules 2017, 22, 2267 3 of 22 Molecules 2017, 22, 2267 3 of 23 nucleotidyl-transferases, ANT) of the molecule, are the leading cause of the rapid increase and nucleotidyl-transferases,dissemination of resistance ANT) [26–30].of the The molecule, first enzyme are the of leadingthis kind cause was of identified the rapid in increase 1967 in and an disseminationEscherichia coli of strain resistance that [possessed26–30]. The an first enzyme enzyme that of this could kind inactivate was identified kanamycin in 1967 inby an transferringEscherichia colian strainacetyl thatgroup possessed to the an 6 enzyme′-N position that couldof the inactivate antibiotic kanamycin molecule. by transferringThe resulting an acetylcompound, group to6′ the-N- 6acetylkanamycin,0-N position of the does antibiotic not have molecule. antibiot Theic resultingproperties compound, [31]. Aminoglycoside 60-N-acetylkanamycin, 6′-N-acetyltransferases does not have antibioticbelong to propertiesthe GNAT [ 31(GCN5-related]. Aminoglycoside N-acetyltransferases) 60-N-acetyltransferases superfamil belongy of to enzymes, the GNAT which (GCN5-related includes Nmore-acetyltransferases) than 100,000 members superfamily found of in enzymes, prokaryotes, which eukaryotes, includes more and than archaea 100,000 [32,33], members remain found a very in prokaryotes,significant cause eukaryotes, of failure and of archaeatreatment [32 of,33 numerous], remain asevere very significant infections cause[26,34]. of More failure than of treatment hundred ofaminoglycoside numerous severe modifying infections enzymes [26,34 ].have More been than identified hundred to aminoglycoside date [26,27]. Among modifying the enzymesmultiple haveapproaches been identified tried to address to date the [26 problem,27]. Among of resistan the multiplece caused approaches by aminoglycoside tried to address modifying the enzymes, problem ofmodification resistance causedof the aminoglycoside by aminoglycoside molecule modifying was enzymes,among the modification most successful of the [35]. aminoglycoside Addition of moleculechemical wasgroups among that thedo mostnot impair successful the [antibiot35]. Additionic activity of chemical of the aminoglycoside groups that do produced not impair new the antibioticcompounds activity that are of thenot aminoglycoside substrate of most produced aminoglycoside new compounds modifying that enzymes are not substrate [35]. These of mostnew aminoglycosidemolecules derived modifying from enzymesnatural [35aminoglycosides]. These new molecules are known derived as from semisynthetic. natural aminoglycosides The first areaminoglycoside known as semisynthetic. of this kind to The be firstused aminoglycoside as an antibacterial of thiswas kind dibekacin, to be used introduced as an antibacterial in 1975 and wasstill dibekacin,in use in various introduced countries in 1975 [36,37]. and In still the in following use in various years, numerous countries [semisynthetic36,37]. In the aminoglycosides following years, numerouswere synthesized semisynthetic with activity aminoglycosides against resistance were synthesized caused withby different activity againstaminoglycoside resistance modifying caused by differentenzymes. aminoglycoside Amikacin, one of modifying the most enzymes.successful Amikacin,semisynthetic one aminoglycosides, of the most successful was synthesized semisynthetic by aminoglycosides,acylation with the was L-( synthesized−)-γ-amino- byα-hydroxybutyryl acylation with the sideL-( −chain)-γ-amino- at theα-hydroxybutyryl C-1 amino group side of chain the atdeoxystreptamine the C-1 amino group moiety of theof kanamycin deoxystreptamine A [38] (Scheme moiety of1). kanamycin A [38] (Scheme1).