Austinn C. Miller, MD1; Susuana Adjei, MD1; Laurie A. Temiz, BA1,2; Stephen K. Tyring, MD, PhD, MBA1,3

1Center for Clinical Studies, Webster, TX, USA
2Meharry Medical College, Nashville, TN, USA
3Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
All authors have no conflicts of interest.

Virtually any antibiotic can be used in dermatology given the broad range of conditions treated. With the widespread use of antibiotics and the rapid emergence of resistant organisms, it is important to understand the mechanisms at play that contribute to resistance.

Key Words:
antibiotic resistance, dermatology, mechanisms of resistance, antibiotic, antimicrobial, infection


The advent of antibiotics is arguably one of the greatest achievements in history, permitting survival among many with infections who would have previously died without intervention. Amid the fields in which the use of antibiotics is particularly widespread lies dermatology. A spectrum of inflammatory and infectious dermatologic conditions have been treated with antibiotics since their inception. The continued success of any therapeutic agent is compromised by the potential development of tolerance or resistance to that compound over time.1 In the case of antibiotics, resistance among bacteria has become a serious issue and has been named one of the greatest threats to human health.2 The number of infections caused by multidrug-resistant bacteria is increasing, and the specter of untreatable infections is now a reality.2 As this number increases, new antibiotic developments cannot match the pace.2

While many factors contribute to the development of resistance, its basis stems from bacterial alterations at the molecular level. Therefore, it is important for dermatologists to understand the mechanisms at play.

Brief Review of Antibiotics in Dermatology and Mechanism of Action

Many antibiotics are utilized in dermatology. Countless isolates of bacteria may cause skin and soft tissue infections (SSTIs) resulting in a wide variety of clinical presentations. Most commonly, superficial cutaneous infections and pyodermas are caused by Staphylococcus aureus (S. aureus) resulting in impetigo, ecthyma, folliculitis, intertrigo, and paronychia. However, other bacterial organisms may also be responsible. Deeper infections like cellulitis, erysipelas, and necrotizing fasciitis are also classically caused by S. aureus or Streptococcus pyogenes, but are also commonly caused by a variety of other gram-positive and negative organisms. Antibiotics may also be used for anti-inflammatory effects, such as with the treatment of acne vulgaris, rosacea, folliculitis decalvans, and hidradenitis suppurativa.

Given the wide variety of conditions treated with antibiotics, nearly the entire gamut may be utilized by dermatologists at some point in time. Understanding the antibiotic mechanism of action is key to understanding mechanisms of resistance (Figure 1, Table 1).

Diagram of bacterial cell, mechanisms of action of commonly used antibiotics in dermatology
Figure 1. Mechanisms of action of commonly used antibiotics in dermatology
Class Mechanism of Action Mechanism of Resistance Resistant Bacteria
Aminoglycosides Bactericidal; Inhibition of 16S ribosomal subunit Target site mutation Mycobacterium tuberculosis
Enzymatic alteration of target Actinomycetes
Chemical alteration of antibiotic Salmonella enterica, Klebsiella pneumoniae, Legionella pneumophila
Beta-lactams Bactericidal; Inhibition of penicillin binding protein (PBP) preventing peptidoglycan cross-linking Complete replacement/bypass of target site Staphylococcus
Destruction of antibiotic Escherichia coli
Decreased permeability Escherichia coli
Epoxides Bactericidal; Inhibition of UDP-N-acetylglucosamine-3- enolpyruvyltransferase (MurA) Destruction of antibiotic Escherichia coli, Pseudomonas aeruginosa, Streptococcus
Glycopeptides Bactericidal; Inhibition of peptidoglycan synthesis Target site mutation Staphylococcus, Streptococcus, Enterococcus
Global cell adaptations Staphylococcus
Lipopeptides Bactericidal; Disruption of the cellular membrane permeability and depolarization Global cell adaptations Staphylococcus, Enterococcus
Lincosamides Bacteriostatic; Inhibition of 23S ribosomal subunit Target protection Staphylococcus
Target site mutation Mycobacterium avium, Helicobacter pylori, Streptococcus pneumoniae
Enzymatic alteration of target Staphylococcus, Enterococcus, Bacteroides
Macrolides Bacteriostatic; Inhibition of 50S ribosomal subunit Target protection Staphylococcus
Target site mutation Mycobacterium avium, Helicobacter pylori, Streptococcus pneumoniae
Enzymatic alteration of target Staphylococcus, Enterococcus, Bacteroides
Destruction of antibiotic Staphylococcus, Enterococcus
Efflux pumps Staphylococcus, some Gram-negative species
Oxazolidinones Bacteriostatic; Prevents initiation complex formation by binding the 23S portion of the 50S ribosomal subunit in such a way that the 30S subunit is blocked from adjoining Target protection Streptococcus
Target site mutation Staphylococcus, Streptococcus, Enterococcus
Enzymatic alteration of target Staphylococcus, Streptococcus
Pleuromutilins Bacteriostatic; Inhibition of 50S ribosomal subunit Target protection Staphylococcus, Streptococcus, Enterococcus
Enzymatic alteration of target Staphylococcus, Enterococcus
Quinolones Bactericidal; Inhibition of DNA synthesis through binding DNA topoisomerase IV and DNA gyrase Target site mutation Staphylococcus, Enterococcus
Target protection Mycobacterium, Enterococcus, Pseudomonas
Rifampin Bactericidal; Inhibition of DNAdependent RNA polymerase (RNAP) Target site mutation Mycobacterium tuberculosis
Streptogramins Bacteriostatic; Inhibition of 50S ribosomal subunit Target protection Staphylococcus, Streptococcus, Enterococcus
Enzymatic alteration of target Staphylococcus, Streptococcus, Enterococcus
Sulfonamides Bacteriostatic (bactericidal when combined with trimethoprim); Inhibition of dihydropteroate synthase (DHPS) (SMX) and dihydrofolate reductase (DHFR) (TMP) Complete replacement/bypass of target site Staphylococcus, Escherichia coli
Tetracyclines Bacteriostatic; Inhibition of 30S ribosomal subunit Target protection Campylobacter, Staphylococcus, Streptococcus, Enterococcus
Efflux pumps Staphylococcus, Streptococcus, Enterococcus, Enterobacter

Table 1. Mechanisms of antibiotic action and resistance among common bacteria

SMX = sulfamethoxazole; TMP = trimethoprim. Modified from: Shah RA. Mechanisms of Bacterial Resistance. In: Tyring SK, Moore SA, Moore AY, Lupi O, editors. Overcoming Antimicrobial Resistance of the Skin. Switzerland: Springer International Publishing; 2021.

Mechanisms of Resistance

Mechanisms by which bacteria evade antibiotic destruction vary in complexity. The most basic method involves mutations in the bacterial target gene, creating a mutant target protein that prevents interaction with the antibiotic, rendering it ineffective.2 Given the intrinsic error prone process of DNA replication/ repair, this type of resistance is inevitable as mutations are bound to occur.3 Resistance may also occur through acquisition of genes encoding proteins that reduce antibiotic binding to molecular targets.2 Bacteria can produce enzymes capable of manipulating molecular targets and blocking antibiotics from binding.2 In addition to modifying the molecular target, bacteria can also reduce the concentration of antibiotics through chemical or enzymatic modification.2 Finally, if an antibiotic target comprises an entity other than a single gene product, resistance to these drugs is attained via retrieval of pre-existing diversity in cell structures and altering their biosynthesis through global cell adaptations.2,3

Modification of Antibacterial Target

Bacteria are capable of modifying any protein that an antibiotic might target.4 Among the most popular antibiotic protein targets is the bacterial ribosome, a complex protein producing machine.5 Bacterial ribosomes consist of dozens of proteins that are arranged into large (50S) and small (30S) subunits.6 Each subunit is associated with specialized ribosomal RNA (50S – 23S, 5S; 30S – 16S). Ribosomes produce proteins through translation – a three-step process: initiation, elongation, and termination.

By targeting ribosomal proteins, antibiotics block protein synthesis in bacteria thus halting proliferation. To survive, bacteria have evolved mechanisms to elude antibiotic protein targeting.

Target Protection

Target protection is a phenomenon whereby a resistance protein physically associates with an antibiotic target to rescue it from antibiotic-mediated inhibition.5 Target protection is an important mode of bacterial resistance to many antibiotics used in dermatology, especially against tetracyclines.7

To disrupt tetracycline action, bacteria deploy ribosomal protection proteins (RPPs) Tet(O) and Tet(M).5 Both of the RPPs are hydrolases that become active in a tetracycline dependent manner. When tetracycline interacts with its ribosomal target, it induces changes in the cellular environment that results in increased affinity of the RPPs to the antibiotic-30S structure.5 The RPPs then hydrolyze antibiotic-30S bonds, dislodging the tetracycline, which permits normal protein synthesis to resume.5

Target Site Modification

By design, antibiotics are selective of target structures. When target structures are modified, chemical properties are altered which change antibiotic target affinity.2 For organisms to survive with resistance, these modifications must result in a loss of target affinity while still maintaining adequate function of normal activities. Most often, this is accomplished by point mutations in genes encoding target sites, enzymatic alterations of binding sites, and replacement or bypass of target sites.2

Mutations of Target Site

Mutations of the 16S portion of the 30S ribosomal subunit target site are the most common form of resistance to aminoglycosides.8 Macrolides are also resisted via target site mutations. The 23S portions of the 50S ribosomal subunit targeted by macrolides can undergo multiple viable mutations.3 Quinolone resistance can occur through target mutation.9 Quinolone resistance determining regions (QRDR) are target gene sequences susceptible to viable mutations that decrease quinolone target affinity.10 Specifically, substitutions in the gyrA and gyrB sequences affect DNA gyrase, while substitutions in parC and parE affect topoisomerase IV.10

Enzymatic Alteration of Target Site

Many different enzymes play a role in antibiotic resistance. One method by which enzymes contribute is through modification of the target site, which results in decreased antibiotic affinity similar to target site mutations. Methylation of strategic nucleotides in the antibiotic binding site weakens antibiotic binding via steric clashes with the modified nucleotide.11 Since some antibiotics share partially overlapping binding sites, methylation of a single nucleotide can result in resistance to multiple antibiotic classes.11

Enzymatic methylation of the ribosome confers resistance to many antibiotics that target the 23S portion of the 50S subunit. Moreover, a specific family of genes encoding for enzymatic methylation may confer resistance against multiple antibiotics that share the same ribosomal binding region.12 For example, the erythromycin ribosomal methylation (erm) gene confers cross resistance to macrolides, lincosamides, and streptogramin B which all bind the same ribosomal site.2 This gene is commonly found in gram-positive cocci and is shared among bacteria via plasmids and transposons. The cfr gene functions similarly to erm, producing a methylation enzyme that provides resistance among gram-positive and gram-negative organisms to oxazolidinones, pleuromutilins, and streptogramin A.2,12

Bypass or Replacement of Target Site

Bypassing of target sites occurs when the target site is changed so that the antibiotic is rendered useless. It may occur through several mechanisms.2 A popular example of resistance to beta (β)-lactams is seen with the mecA gene in Staphylococcus aureus.2,13 This gene results in replacement of normal penicillin-binding proteins (PBPs) with PBP2a that has a low affinity for β-lactams. Its induction occurs in the presence of β-lactams.2,13

Antibiotic Alteration

One method of resistance that bacteria can employ is antibiotic alteration. This is done through enzymatic modification or degradation.2,14 Inactivating modifications interfere with antibiotic-target site binding and include acetylation, phosphorylation, glycosylation, and hydroxylation.2,14 Enzymatic degradation results in the destruction of antibiotics.2

Aminoglycosides are subject to modification through aminoglycoside modifying enzymes (AMEs).2,14 AMEs consists of acetyltransferases, adenyl transferases, and phosphotransferases.2 β-lactams are subject to degradation via β-lactamases.15 In gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, rendering β-lactams useless.15 β-lactamases can be encoded intrinsically (chromosomal) or disseminating on mobile genetic elements like plasmids across opportunistic pathogens.15 In the more recent past, β-lactamases have extended beyond penicillins and cephalosporins to carbapenems.15 Macrolide resistant bacteria have developed enzymes, such as erythromycin esterases, that cleave essential ester bonds and thus disrupt macrolide structure.16 The genes encoding these enzymes are found on mobile genetic elements, establishing the potential for widespread resistance.16

Membrane Permeability Variation

Antibiotic resistance can be mediated by changes to the cell membrane permeability.17 This can be done through alteration in lipid, porin, and transporter structures such as efflux pumps.2

To gain entry into the bacterial cells, antibiotics like β-lactams cross the lipid bilayer of the cell membrane via porins, whereas other lipophilic antibiotics such as macrolides traverse the bilayer via diffusion.3 Alterations to porins or lipid structure result in permeability changes that potentiate resistance. Some gram-negative bacteria intrinsically express full length lipopolysaccharide that prevent diffusion of lipophilic antibiotics.18

Porin mediated resistance is achieved through decreasing the rate of antibiotic entry.2 Loss of porin function can be acquired via changes in OmpF porin protein resulting in replacement/loss of major porins and reduced permeability.19

Efflux pumps extrude toxic compounds out of bacterial cells, including antibiotics.2 A variety of efflux pumps exist and are seen in both gram-positive and gram-negative organisms.17 In clinically important bacteria, such as multidrug-resistant (<MDR) Mycobacterium tuberculosis, methicillin-resistant S. aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa, efflux pumps have critical roles in ensuring bacterial survival and evolution into resistant strains.17

Global Cell Adaptations

Instead of a specific change in one cellular process, some bacteria have developed resistance to antibiotics via global cell adaptations. Through years of evolution, bacteria have developed sophisticated mechanisms to cope with environmental stressors and pressures in order to survive hostile environments.2 This involves very complex mechanisms to avoid the disruption of vital cellular processes such as cell wall synthesis and membrane homeostasis.2 The two main examples of global cell adaptation resistance occur with lipopeptides and glycopeptides.2

Lipopeptides have a multifaceted mechanism of action that results in disruption of cell membrane homeostasis.20 Activity correlates with the levels of calcium and phosphatidylglycerol in the membrane.20 Resistance can be accomplished in some organisms via alteration in cell membrane charge and downregulation of phosphatidylglycerol.20

Glycopeptides are susceptible to resistance via multiple adaptations observed with S. aureus including increased fructose utilization, increased fatty acid metabolism, decreased glutamate availability, and increased expression of cell wall synthesis genes.2 These global adaptations result in reduced autolytic activity, a thickened cell wall, and an increased amount of free D-Ala-D-Ala, all of which reduce effective activity of glycopeptides.2


Awareness of the molecular mechanisms of antibiotic resistance among bacteria is necessary to understand the etiology of antibiotic resistance in dermatology at the most basic level.


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