Antibiotic Resistance

Antibiotic Resistance

Guojun(Daniel) Wang                       

Abstract Antibiotic resistance is becoming more and more common and causing a worldwide threat to people’s health. This review conclude the general structure of bacteria according to their cell wall characteristics as well as two main mechanisms of antibiotic resistance, naturally resistance and acquired resistance, including forming a permeability barrier, increasing the efflux pumps, modification of targets of bacteria or direct modification of the antibiotics such as hydrolysis or adding a chemical group, horizontal gene transfer which is promoted by conjugal system and SOS response.

Introduction Antibiotics are powerful drugs that are used to kill or inhibit the growth of bacteria. The first antibiotic called penicillin was invented in 1928 by a British scientist, Alexander Fleming, and it was first available in the market in 1942. Since then, antibiotics have been commonly used in the hospitals and community. Proper using of antibiotics prevents many lethal diseases from common bacterial infections. However, the overuse and misuse of antibiotics have been a common phenomenon over the past 60 years. This lead to a worldwide antibiotic resistance (AR) problem. The first AR case was observed in 1947 against penicillin, only four years after it was mass-produced.

Antibiotic resistance (AR) refers to the ability of bacteria to resist the antibiotics which had strong effect on killing or inhibiting the original bacteria. Bacteria can naturally acquire the resistance, gain it through the genetic mutation or receive it from other bacteria through conjugation. Some bacteria can be resistant to several types of antibiotics, and these bacteria are termed as “superbugs.” All these resistant bacteria are more difficult to treat than normal strains. Therefore, learning the basic structure of bacteria and how bacteria become resistant to certain antibiotics can help us understand the AR mechanisms better.

Bacteria are divided into two groups based on their cell wall: Gram-positive and Gram-negative bacteria [Figure 1]. Both bacteria have cell wall and plasma membrane. Gram-positive bacteria contain cytoplasmic membrane surrounded by a tough and rigid mesh called cell wall. In contrast, Gram-negative bacteria contain thin cell wall that is surrounded by a second lipid membrane called outer membrane (OM). All these structures have their own functions. The function of the cell wall is to maintain the characteristic shape of a bacterium and protect it from mechanical and osmotic stresses. The plasma membrane maintains the stability of bacterial components by controlling the entry and export of ions to the cell. In Gram-negative bacteria, OM serves as an extra protective layer, which prevents large substances from entering into the cell. However, this membrane contains many channels called porins, which allow the entry of small molecules, such as antibiotics.[1]

[pic 1]

Figure 1 Basic structure of Gram-positive and Gram-negative bacteria

Antibiotic Resistance   

Bacteria can be naturally resistant to specific antibiotics but also can acquire resistance to antibiotics through horizontal gene transfer or the mutations in chromosomal genes. The natural resistance refers to the ability of bacteria to resist certain antibiotics due to structural or functional characteristics. For example, some bacteria can prevent the antibiotics from accessing to the target, including forming a permeability barrier[2,3] or increasing the function of bacterial efflux pumps. AR can also happen through modifying to the target, or through metabolizing the antibiotics which change its chemical composition via hydrolysis or transferring of a chemical group. In addition to natural resistance, bacteria can acquire the resistance through genetic mutations which change the antibiotic targets or via the horizontal gene transfer which is promoted by the conjugal system,[4] and SOS response.

In this review, I will summarize commonly seen AR mechanisms.

I. Prevention of antibiotics from accessing the targets, which can occur via two routes：

Increasing the function of permeability barrier Gram-negative bacteria are naturally less permeable to many antibiotics because their OM forms a permeability barrier. Antibiotics which have a strong affinity for water can cross the OM by diffusing through the porin proteins. Particularly, small hydrophilic molecules such as β-lactams and quinolones can cross the OM only through porins.[5] Therefore, decreasing the permeability of the outer membrane and limiting antibiotic entry into the bacterial cell are achieved by the down-regulation of porin channels or by the replacement of porins with more-selective channels. In Enterobacteriaceae, Pseudomonas spp. and Acinetobacter spp. are usually resistant to newer drugs such as carbapenems and cephalosporins through enzymatic degradation.[6-10] However, a new interesting finding showed that this resistance can be acquired as a result of a reduction in porin expression. For example, Enterobacteriaceae spp. are resistant to carbapenem in the lack of carbapenemase if mutations reduce the porin production or mutant porin alleles are present.[7,11] Increasing the function of bacterial efflux pumps The function of the bacterial efflux pumps is to transport many antibiotics out of the cell and maintain a low-intracellular concentrations of antibiotics.[12] They are also the main contributors to natural resistance of Gram-negative bacteria to various antibiotics that are used to treat Gram-positive bacterial infection. Unlike porins which are present in the OM, efflux pumps are present in the cytoplasmic membrane.  When overexpressed, efflux pumps cause high levels of resistance to previously useful antibiotics. Antibiotics of all classes except polymyxin are susceptible to the activation of efflux systems.[13] When these antibiotics are entering the cell, the efflux pumps will pump them out before they reach their target.[14] Some efflux pumps have narrow substrate specificity, but most pumps can transport a lot of structurally dissimilar substrates , thus causing antibiotic resistance. These type of pumps are known as multidrug resistance (MDR) efflux pumps.[12]

II. Modification to the target

The natural modification of the antibiotic target is shown to be an effective method of antibiotic resistance that does not need a mutant gene encoding the target molecules. In recent years, protection of targets through modification has been found to be a clinically relevant mechanism of resistance for several antibiotics. A common protection is the modification of target ribosome by methylation. For example, the chloramphenicol-florfenicol resistance (cfr) methyltransferase is an enzyme which specifically methylates A2503 in the 23S rRNA, causing resistance to many drugs that have targets near this site, including phenicols, oxazolidonones, pleuromutilins, streptogramins, and lincosamides.[15] Similarly, the erythromycin ribosome methylase (erm) family of genes methylate 16S rRNA and alter the drug-binding site, thus preventing the binding of macrolides, lincosamines and streptogramins.[16]