**5. References**

100 Antimicrobial Agents

against efflux-mediated resistant *S. pyogenes*, comparable to azithromycin.

**12f**

*Streptococcus pneumoniae M*

Fig. 7. Antibacterial activity of 3-decladinosyl-3-hydroxy ureas and thioureas on

Novel decladinosyl azalides

3-Decladinosyl azithromycin (**16**)

**(±)- 11h**

azithromycin (**1**) and 3-decladinosyl azithromycin (**16**).

Azithromycin (**1**)

**33a (±)- 33c**

**11f**

≥64

32

16

8

4

2

MIC μg/ml

we termed *"decladinosylides."*

their parent 3-cladinosyl analogues (Bukvić Krajačić et al., 2009) and test standards

*S. pneumoniae* efflux-mediated resistant strain (Bukvić Krajačić et al., 2011) in comparison to

**35a 34b 36d**

Cladinosyl analogues of novel decladinosyl azalides

**13g 13c**

3-OH

**1**

**16**

3-Cladinosyl

• Contrary to the well known fact (LeMahieu, et.al., 1974; Kaneko et.al., 2006; Pal, 2006; Tanikawa, et.al., 2001; Mutak, 2007) and previous results (Bukvić Krajačić et al., 2005, Bukvić Krajačić et al., 2007; Marušić Ištuk et al., 2007), that simple removal of cladinose sugar from macrolides significantly decreases antibacterial activity, unexpectedly, some of the newly discovered 3-decladinosyl-3-hydroxy ureas **33** & **34**, and thioureas **35** & **36** (Bukvić Krajačić et al., 2011) maintain good antibacterial activity against panel of key respiratory Gram-positive and Gram-negative pathogens. Against efflux-mediated resistant *S. pneumoniae* strain they posses comparable or better activity (MIC 2 -16 µg/ml) to their 3-cladinosyl parent analogues **11** & **13** (MIC 4 -16 µg/ml) (Bukvić Krajačić et al., 2009) and azithromycin (**1**) (MIC 8 µg/ml), and significantly better in comparison to the inactive 3-decladinosyl azithromycin (**16**) (MIC >64 µg/ml) (Fig. 7) (Bukvić Krajačić et al., 2011). Also, some 3-decladinosyl-3-hydroxy ureas **33** & **34**, and thioureas **35** & **36**, maintain antibacterial activity against Gram-negative pathogens *H. influenzae* and *M. catarrhalis* in comparison to their parent 3-cladinosyl derivatives (Bukvić Krajačić et al., 2009), and comparable to azithromycin, but demonstrate a large improvement in comparison with inactive 3-decladinosyl azithromycin **16** (Bukvić Krajačić et al., 2011) and other 3-decladinosyl derivatives reported in literature. These small library of 3-decladinosyl-3-hydroxy ureas and thioureas of 15-membered azalides

on *S. pneumoniae efflux-mediated and S. pyogenes* iMLS resistant strains in comparison to azithromycin (Fig 7). Among them, new ureas with naphtyl substituents (**11f, 11g** & **11h**) showed better activity against inducible resistant *S. pyogenes* in comparison to azithromycin. Ureas **11f** & **11g** and thioureas **12c, 12d, 12e** and **12f** possess good activity


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Hybrid Series: Influence of the Central Linker on the Antibacterial Activity, *ACS* 


**6** 

*Portugal* 

**Antimicrobial Activity of Condiments** 

*Department of Microbiology, Faculty of Pharmacy, University of Lisbon* 

The phenomenon of antibiosis, life prevents life, observed by Goubert and Pasteur in 1877, gave rise to the use of antibiotics in therapy. In fact, on that date has been found that certain microorganisms were sensitive to the action of products produced by other microorganisms. Unfortunately, many of these products were toxic to the cells of higher animals, and only in 1943, the first antibiotic isolated and studied by Sir Alexander Fleming - penicillin G – was introduced in clinic. Penicillin was discovered in 1929 when Fleming sought potential antibacterial compounds. He noted that a colony of the fungus *Penicillium notatum* had grown up on a plate containing the bacterium *Staphylococcus aureus* and around the fungus had a zone where the bacteria did not grow. The active substance, Fleming called penicillin, but could not isolate it. Several years later, in 1939, Ernst Chain and Howard Florey developed a way to isolate penicillin and used it to treat bacterial infections during the Second World War. The new drug came into use in the clinic in 1946 and had a huge impact on public health. Its discovery and development revolutionized modern medicine and

paved the way for the development of many more antibiotics of natural origin.

disruption or peptidoglycan synthesis inhibition) or by inhibiting their growth.

Antimicrobial activity is understood as the ability of some agents to eliminate microorganisms (aiming at different metabolic or structural targets, as nucleic acid synthesis

Before the introduction of antibiotics in the 1940s, infections were rare, but rapidly increased in frequency as increased the use of antibiotics. In fact, most antibiotics that were first used in the 1940s and 1950s are no longer used clinically because nowadays the resistance of infectious beings to these antibiotics is very common. Over time they have been developing new antibiotics and with the introduction of each, new drug-resistant bacteria appeared rapidly. Today, we moved the mode of use and prescription of antibiotics in order to try to slow the relentless pace of bacterial evolution, but not yet found a solution to this problem. Microbiologists continue to study how bacteria evolve so that we can predict how they will respond to medical treatment and so we can better manage the evolution of infectious

This microbiocidal or microbiostatic activity is, on one's mind, usually related with therapeutic objectives or sanitizing activities within the food or pharmaceutical industries. Nevertheless, in our daily routine, and also linked with food microbiology, we are faced with a number of substances, which we use only as culinary additives, that may work as antimicrobial agents or may turn to be a good source of new antimicrobial molecules for

**1. Introduction** 

diseases.

André Silvério and Maria Lopes

malarial parasite apicoplast as the target of azithromycin. *Journal Biological Chemistry,* Vol. 282, (November 2006), pp. 2494-2504, ISSN 0021-9258

